Skin Lightening Compositions

ABSTRACT

Compositions and methods for lightening and/or depigmenting skin are provided, the compositions comprising compounds having the structure: 
     
       
         
         
             
             
         
       
     
     or having the structure: 
     
       
         
         
             
             
         
       
     
     as defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. Ser. No.12/984,159, filed Jan. 4, 2011, and currently pending, which claimspriority from U.S. Provisional Patent Application Ser. No. 61/292,577,filed Jan. 6, 2010.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to novel topically applicable cosmeticand/or dermatological compositions comprising depigmenting agents fortreating the skin of the face and/or body for the purposes of lighteningthe skin, evening skin tone and/or treating areas of hyperpigmentation.More specifically, the depigmenting agents are inhibitors of Type I H+,K+-ATPases.

2. Description of the Prior Art

Consumers of skin lightening products spend more than $1 billionannually in search of Skin with an even tone on their faces, hands andbodies. The development of areas of hyperpigmentation on the skin isobviously of great concern to these individuals. The hyperpigmentedareas are caused by a concentration of melanin in the keratinocyteslocated at or near the skin surface. Melanin pigment is produced inmelanocytes in highly specialized organelles known as melanosomes.Melanocytes are found in several locations throughout the body,including in the bottom layer of the skin's epidermis, the iris of theeye and the hair. Manufacturing of melanin begins when melanin-makingenzymes are activated and transform the amino acid tyrosine tointermediates of the end product, melanin. The actual production ofmelanin begins in the melanosomes. Inside human melanosomes, a series ofchemical reactions, catalyzed by enzymes, converts tyrosine into twotypes of melanin, eumelanin, which is brown or black in color, andpheomelanin, which is red or yellow. The mechanism of formation ofmelanin includes the following principal mechanisms:

Tyrosinase is the essential enzyme involved in this reaction sequence.It catalyzes the conversion of tyrosine into dopa(dihydroxyphenylalanine) and the conversion of dopa into dopaquinone.

Once the melanosomes are loaded with melanin, the melanosomes aretransported along a secretory pathway to their final destination inkeratinocytes, which are barrier cells in the uppermost layer of theskin, and into the hair, and to other locations in the body. The amountof melanin transported and the mix of the pigments determines skin, eyeand hair color in humans. Melanin functions to protect DNA in skin cellsby absorbing ultraviolet radiation which can damage the DNA, and leavethe skin vulnerable to cell damage, including sunburn, premature agingand skin cancer.

Various depigmenting agents having differing mechanisms of action andlevels of efficacy are known. Depigmenting agents may act directly onepidermal melanocytes, such as by destroying these cells. One such agentis hydroquinone and its derivatives. Hydroquinone also competes fortyrosine oxidation in active melanocytes. Although highly efficacious asdepigmenting agents, the use of these compounds, in view of theircytotoxicity, is legally limited to a concentration of 2% without aprescription in the U.S., and is not available over the counterelsewhere. Examples of other depigmenting agents include kojic acid,which chelates the copper ion in the active site of tyrosinase; butwhich tends to be unstable in the processing of cosmetics; hydrogenperoxide, which inhibits melanogenesis because it bleaches the melaninbut which is unstable; ascorbic acid, which converts dopaquinone back todopa, but which has low activity and low stability; salicylic acid andlactic acid, which increase cell turnover; and unsaturated fatty acids,such as linoleic acid, which affect the processing and function oftyrosinase in connection with the ubiquitin-proteasome pathway.

Other depigmenting agents include those which interfere with one or moresteps in the production of melanin. These agents may act by inhibitingone or more enzymes (e.g. tyrosinase) involved in melanogenesis or byinserting themselves in the synthetic chain as a structural analogue ofone of the chemical compounds. Still other depigmenting agents may actby disrupting tyrosinase processing and sorting through the secretorypathway (translocation through membrane-bound organelles, e.g.,endoplasmic reticulum Golgi endosomes melanosomes in melanocytes). Afurther depigmenting mechanism could involve the modulation oftyrosinase messenger RNA (mRNA) transcription and itspost-transcriptional stability. Depigmenting agents may also act bydecomposing already formed melanin.

During routine screening of compounds for inhibition of melanogenesis incultured B16F10 mouse melanoma cells, it was unexpectedly discovered bythe inventors that a class of compounds called substitutedbenzimidazoles all strongly inhibited melanogenesis. This was quitesurprising since the only activity known for these compounds is thespecific inhibition of the proton pump protein reportedly only found inthe apical cytoplasmic membrane of gastric parietal cells (Olbe, L.,Carlsson E., Lindberg P. A Proton-Pump Inhibitor Expedition: The CaseHistories of Omeprazole and Esomeprazole, Nature Reviews Drug Discovery,2:132-9, 2003). The gastric proton pump has never been found inmelanocytes and the inventors were unable to detect its gene expressionin melanocytes. Another gastric proton pump inhibitor, a substitutedimidazopyridine compound with a different reactive site, was tested andit also surprisingly inhibited melanogenesis. This led the inventors toconsider, for the first time, using gastric proton pump inhibitors todepigment skin.

Recent studies have suggested that differences in epidermal pigmentationmay be due to differences in melanosomal pH. However, the literature hasbeen contradictory as to whether melanogenesis is favored by acidic orbasic pH. On the one hand, it has been observed that melanosomes arenormally acidic (Brilliant, M. and Gardner, Melanosotnal pH, Pink LocusProtein and their Roles in Melanogenesis, J. of Invest. Dermatol. 117(2)2001; Moellmann, G., Slominski, A., Kuklinska, E., Lerner A. B.:Regulation of Melanogensis in Melanocytes. Pigment Cell Res., 1:79-87,1988; Bhatnagar, V., Anjaiah, S. Puri, N, Arudhra Darshanam, B. N., andRamaia, A.: pH of Melanosomes of B16 Murine Melanoma is Acidic: ItsPhysiological Importance in the Regulation of Melanin Biosynthesis,Arch. Biochem. Biophys. 307:183-192, 1993; Ramaiah, A.: Lag Kinetics ofTyrosinase: Its Physiologic Implications, Indian J. Biochem. andBiophys. 33:349-356, 1996), and that the acidification of variousintracellular compartments is important for a number of processes (VanDyke, R. W.: Acidification of Lysosomes and Endosomes, Sub-CellularBiochem., 27:331-360, 1996; Grabe, M. and Oster, G.: Regulation ofOrganelle Acidity, J. General Physiol. 117:329-344, 2001). Devi et al.proposed that since melanosomes can be acidic, low melanosomal pHfacilitates melanogensis, and therefore tyrosinase activity is optimalat acidic pH and inactive at neutral pH (Devi, C. C., Tripathi R. K.,Ramaia, A, pH-dependent Interconvertible Allosteric Forms of MurineMelanoma Tyrosinase: Physiological Implications. Eur. J. Biochem.166:705-711, 1987). Very recently, Gunathilake, et al. reported thatmelanocytes, and particularly the dendrites, from darkly pigmentedsubjects are significantly more acidic than those from lightly pigmentedsubjects, and that this acidity appears to be localized to melanosomes(Gunathiliake R., Schurer N., Shoo B., Celli, A., Hachem J. P., CurmrineD., Sirimanna, G., Feingold K., Mauro t., Elias P.: pH-regulatedMechanism Accounts for Pigment-Type Differences in Epidermal BarrierFunction. J. Invest. Dermatol, 129:1719-1729, 2009). On the other hand,other groups have observed that mammalian tyrosinase has optimalenzymatic activity at near neutral pH and that its activity is lost withdecreasing pH (Hearing, V. J. and Ekel, T. M.: Mammalian Tyrosinase. AComparison of Tyrosine Hydroxylation and Melanin Formation, J. Biochem.,157:549-557, 1976; Saeki, H. and Oikawa, A.: Stimulation of Ionophoresof Tyrosinase Activity of Mouse Melanoma Cells in Culture, J. Investig.Dermatol. 85:423-425, 1985; Townsend, D., Guillery, P., and King. R. A.:Optimized Assay for Mammalian Tyrosinase (Polyphenol Phenyloxidase),Anal. Biochem. 139:345-352, 1984). Ancans et al., reported that nearneutral melansomal pH is optimal for human tyrosinase activity,melanogenesis and maturation rate of melanosomes, and that low pHsuppresses melanin production in Caucasian melanocytes. It was furtherobserved that the ratio of eumelanin/phaeomelanin production and thematuration rate of melanosomes are regulated by melanosomal pH, and thattherefore, melanosomal pH appears to be an essential factor whichregulates multiple stages of melanin production (Ancans, J, D., Tobin,J., Hoogdujin, J. J. Smit, N. P., Wakamatsu, K., and Thody, A. J.:Melanosomal pH Controls Rate of Melanogenesis, Eumelanin/PhaeomelaninRatio and Melanosome Maturation in Melanocytes and Melanoma Cells,Experimental Cell Research 268:26-35, 2001). Studies by Smith et al.also suggested that the internal pH of melanosomes in Caucasians isacidic, and at this pH tyrosinase is inactive, while the pH ofmelanosomes of Blacks appears to be more neutral and optimal fortyrosinase activity (Smith et al.: The Relationship Between Na+/H+Exchanger Expression and Tyrosinase Activity in Human Melanocytes.Exptl. Cell Res. 298:521-534, 2004). Thus, there is disagreement in theliterature as to the role of melanosome pH in the production of melanin.

Puri et al. reported the aberrant pH of mouse “p” gene (pink-eyeddilution (p) mutant) melanocytes, and, based on a finding of feweracidic melanosomes, hypothesized that the p protein functions in theacidification of melanosomes, e.g., an ion-exchange or channel protein,in the melanosomal membrane, which may affect the activity and/orrouting of tyrosinase (Puri, N., Gardner, J. M., Brilliant, M. H.:Aberrant pH of Melanosomes in Pink-eyed Dilution (p) Mutant Melanocytes.Soc. Invest. Dermatol. 115:607-613, 2000). Ancans et al. suggestedalternative hypotheses to Puri, since p-protein does not utilize energyfrom ATP which would enable it to function as an ionic transporteragainst a proton gradient. Ancans et al. treated mutant and wild-typemelanosomes with v-type proton pump inhibitors (responsible fororganelle acidification), and observed that, in mutant cells,neutralization resulted in increased melanin content, while there was nosignificant change in the wild-type cells. The study suggested thatP-locus protein has a role in creating a near neutral localmicroenvironment and that this change facilitates tyrosinase activity.Thus, p-locus protein may function as a channel to reduce the protonconcentration inside the melanosome analogous to Na+/H+ antiporters(NHEs), (Ancans, J., Hooduijn, J., Thody, A. J.: Melanosomal pH, PinkLocus Protein and their Roles in Melanogenesis. J. Invest. Dermatol.117(1):158-159, 2001). Halaban et al., suggested that bafilomycin A1 andmonensin play dual roles in the processing of tyrosinase: reduction oflevels of tyrosinase retained in the endoplasmic reticulum andfacilitating the release of tyrosinase from the endoplasmic reticulum tothe Golgi by increasing the pH in either the endoplasmic reticulum orthe endoplasmic reticulum-Golgi intermediate compartment (Halaban, R.,Patton, R. S., Cheng, E., Svedine, S., Trombetta, E. S., Wahl, M. L.,Arujan, S. and Hebert, D. N.: Abnormal Acidification of Melanoma CellsInduces Tyrosinase Retention in the Early Secretory Pathways, J. Biol.Chem. 277(17):14821-14828, 2002).

Thus there is no clear guidance from the literature as to whetherincreasing or decreasing the pH of acidic organelles includingmelanosomes would benefit depigmentation. Even if one hypothesized thatagents which inhibit the neutralization of pH in melanocytes might bedesirable, prior to the present invention, there was no recognized meansby which to reduce the pH of the acidic organelles, and therefore,certainly none that were safe. The available pH adjusting compounds suchas bafilomycin A1 and monensin increase the pH of acidic organelles, andthe known target for the gastric proton pump inhibitors is not presentin melanocytes.

SUMMARY OF THE INVENTION

This invention relates to safe and effective compounds and compositionswhich achieve skin lightening or depigmenting in skin, and to theirmethods of use.

Specifically, the invention relates to compositions comprising a skinlightening or depigmenting effective amount of at least one compoundrepresented by the structural formula:

wherein:

R₁ and R₂ are same or different and are each selected from the groupconsisting of hydrogen, alkyl, carbomethoxy, carboethoxy, alkoxy, andalkanoyl, any of which may be halogen-substituted, and halogen;

R₆ is selected from the group consisting of hydrogen, methyl, and ethyl;and

R₃, R₄ and R₅ are the same or different and are each selected from thegroup consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy,ethoxyethoxy, propoxy, propoxymethoxy, and the like, any of which may behalogen-substituted;

or a derivative or physiologically acceptable salt, solvate orbioprecursor, or stereoisomer or enantiomer thereof; or by thestructural formula:

wherein:

R₂ is hydrogen, lower alkyl or hydroxy lower alkyl;

R₃ is lower alkyl, —CH₂CN, hydroxy lower alkyl, —NO, —CH₂N═C or

(wherein R₆ and R₇ are independently selected from the group consistingof hydrogen and lower alkyl) or hydrogen provided R₂ is not hydrogen;

R₄ is Z-T-W wherein Z represents —O—, —NH— or a single bond; Trepresents a straight- or branched-chain lower-alkylene group; when Z isa single bond, T also represents an ethenylene or a propenylene groupwherein the unsaturated carbon is at the single bond; when Z is —O—, Talso represents an allylene group wherein the saturated carbon is at theoxygen; and W represents hydrogen, when T is allylene and Z is —O—, andAr, wherein Ar is selected from thienyl, pyridinyl, furanyl, phenyl andsubstituted phenyl wherein there are one or more substituents on thephenyl independently selected from halogen or lower alkyl; and

R₅ is hydrogen, halogen or lower alkyl;

or a derivative or physiologically acceptable salt, solvate orbioprecursor, or stereoisomer or enantiomer thereof;

formulated into a topically applicable, cosmetically or dermatologicallyacceptable vehicle, carrier or diluent therefor.

Included in this invention are pharmaceutically-, cosmetically- anddermatologically-acceptable salts of the above compounds, stereoisomersand enantiomers thereof free from or mixed with other enantiomers orstereoisomers and such compounds in compositions with a cosmetically-,dermatologically- or pharmaceutically-acceptable carrier thereof.

This invention further relates to methods of lightening or depigmentingskin by administering to the skin in need thereof a compositioncomprising a safe and effective amount of a skin lightening ordepigmenting active as described herein.

The compositions of the invention may consist essentially of the skinlightening or depigmenting active compound. By “consisting essentiallyof”, it is intended that the compositions of the invention do notinclude any component which would adversely affect the desiredproperties imparted to the compositions by the active skin lightening ordepigmenting compound.

As used herein, the term “topical application” means directly layeringon or spreading on outer skin.

As used herein the term “cosmetically or dermatologically acceptable”means suitable for use in contact with skin without undue toxicity,incompatibility, instability, irritation, allergic response, and thelike, commensurate with a reasonable benefit/risk ratio.

As used herein, the term “hyperpigmented region” means a localizedregion of the skin having high melanin content.

As used herein, the term “skin-lightening” or “skin depigmenting” meansdecreasing melanin in skin, including overall lightening of skin toneand lightening of hyperpigmented regions, including age spots, melasma(chloasma), freckles, post-inflammatory hyperpigmentation or sun-inducedpigmented blemishes, and the like.

As used herein the term and “safe and effectiveskin-lightening/depigmenting amount” means an amount of compound orcomposition sufficient to significantly induce a positive modificationin the condition to be treated (i.e., lightening skin or evening skintone), but low enough to avoid serious side effects.

As used herein the term “derivative” means physiologically acceptablesalt, solvate or bioprecursor thereof, and the like.

BRIEF DESCRIPTION OF THE DRAWING

The FIGURE is a graph illustrating the skin lightening effect of acomposition of the invention as compared with a positive control.

DETAILED DESCRIPTION OF THE INVENTION

Inhibitors of gastric acid secretion can be classified into two generalcategories based on their site of action; inhibitors working at thebasolateral membrane of the gastric parietal cell, such as histamineH₂-receptor antagonists or anticholinergic agents, and those working atthe secretory membrane, such as inhibitors of the Type I K+/H+-ATPase,also known as the proton pump or p-pump of the parietal cell. The p-pumpinhibitors include reversible and irreversible types. Recently, thesubstituted benzimidazoles, agents belonging to the latter class, havereceived much attention.

Certain substituted benzimidazole compounds are generally known asgastric acid inhibitors or gastroesophageal reflux disease (GERD) andulcer medications. They are also referred to as proton pump inhibitorsor PPIs. PPI products currently on the market include omeprazole, 5- or6-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole;esomeprazole, S-5-methoxy-2-{(4-methoxy-3,5 dimethylpyridin-2-yl)methylsufinyl]-3H-benzoimidazole; lansoprazole,2-{[3-methyl-4-(2,2,2-trifluoroethoxyl)pyridin-2-yl]methylsulfinyl-1H-benzo(d)imidazole; pantoprazole,RS-6-(difluoromethoxy))-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-1H-benzo(d)imidazole;and rabeprazole (pariprazole),2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzo(d)imidazole.The PPIs are safe and have been observed to be more effective inreducing stomach acid than the H₂-receptor blockers. A particularlypopular PPI is omeprazole, also known as Prilosec®. Other PPIs includeleminoprazole, 2-((o-(isobutylmethylamino)benzyl)sulfinyl)benzimidazole;and timoprazole, 2-(pyridine-2-ylmethylsulfinyl)-1H-benzimidazole.

All of these PPI compounds contain a basic structural framework anddiffer only in the nature of substituents placed on the pyridine andbenzimidazole rings as shown by the following formula:

Commonly used PPIs are shown by the following formulas:

The PPIs are compounds that block the gastric hydrogen potassium ATPaseor H+/K+-ATPase, the enzyme primarily responsible fir the acidificationof the stomach contents. This ATPase is found in parietal cells whichare highly specialized epithelial cells in the inner cell lining of thestomach. This ATPase moves acid across the gastric mucosa and gastricparietal cells (Chang, H., Saccomani G., Rabon, E., Schackmann R.,Sachs, G.: Proton Transport by Gastric Membrane Vesicles, Biochim etBiophysica Acta, 464(2):313-327, 1977; Sachs G. and Wallmark, B., TheGastric H+K+ ATPase: The Site of Action of Omeprazole. Scand. J. ofGastroenterol., 24: No. s166, 3-11, 1989). Parietal cells possess asecretory membrane system and the H+/K+-ATPase is the major proteinconstituent of these membranes. The ATPase undergoes a cycle ofphosphorylation and dephosphorylation coupled to the outward movement ofH+ (from the cytoplasm of the parietal cell) and the inward movement ofK+ (from the gastric lumen) in a net electroneutral fashion. The ATPasefunctions as an ion pump to transport ions against a concentrationgradient using energy derived from the hydrolysis of ATP. As with allp-type ATPases, a phosphate group is transferred from adenosinetriphosphate (ATP) to the H+/K+-ATPase during the transport cycle. Thephosphate transfer powers a conformational change in the enzyme thathelps drive ion transport. The PPIs act by irreversibly blocking the H+,K+-ATPase (Robinson, M. and Home, J.: Clinical Pharmacology of ProtonPump Inhibitors: What the Practicing Physician Needs to Know, Drugs:63:2739-2754, 2003), thereby inhibiting the secretion of acid into thestomach. These anti-secretory compounds specifically inhibit the ATPaseat the secretory surface of the gastric parietal cell, blocking thefinal step of acid production.

Unlike H₂-antagonist compounds that interact competitively andreversibly with H₂ receptors, the PPI, in the acidic environment of thestomach, forms a covalent disulfide bond with the ATPase enzyme, leadingto an irreversible inhibition of the pump. One sulfur atom in thedisulfide bond will come from a cysteine residue (CYS) on the ATPase andthe other will come from the PPI. CYS813 has been identified as theresidue most critical to the inhibiting action of the PPIs. Thiscysteine is located in the luminal vestibule of the ATPase and isaccessible from the extracytoplasmic area of the ATPase protein. SomePPIs also will react with CYS822. Additional residues on the enzyme arealso important for holding and positioning the PPI in place. (Roche, V.F.: The Chemically Elegant Proton Pump Inhibitors, Amer. J. Phar. Educ,70(5) Article 101, 2006; Qaisi, A. M., Tutunji, J. F., Tutunji, L. F.:Acid Decomposition of Omeprazole in the Absence of Thiol: a DifferentialPulse Polarographic Study at the Static Mercury Drop Electrode (SMDE),J. Pharm. Sci. 95(2):384-391, 2006). The PPI must be activated to bindwith the ATPase; that is, the PPI requires an acidic environment toundergo the re-arrangement to the active form. As shown in the schemebelow, the activation pathway begins with two protonation reactionswhich readily occur immediately outside the highly acidic parietal cell.The sulfonamide (protonated) form of the PPI binds to thiol groupswithin the alpha subunit of the ATPase to form relatively stabledisulfides. (Besancon, M., Shin, J. M., Mercier, F., Munson, K., Miller,M., Hersey, S., Sachs, G.: Membrane Topology and Omeprazole Labelling ofthe Gastric H+, K(+) Adenosinetriphosphatase. Biochem. 32(9):2345-2355,1993; Besancon, M., Simon, A., Sachs, G., Shin, J. M.: Sites of Reactionof the Gastric H, K-ATPase with Extracytoplasmic Thiol Reagents. J. ofBiol. Chem. 272:22438-446. 1997).

The reversible type proton pump inhibitors are the APAs (acid pumpantagonists), also, but less accurately, referred to as P-CABs(potassium competitive acid blockers), since not all APAs will bestrictly potassium competitive. The major classes of these reversibleinhibitors include imidazopyridine derivatives, acyl quinolinederivatives and pyrrolopyridazine derivatives.

Since pH is an important factor in melanogenesis, and consumers desirousof an even skin tone are always looking for more efficacious and safeproducts, the present inventors investigated whether inhibitors of TypeI H+, K+-ATPases, such as, substituted-benzimidazoles, including the2-pyridylmethylsulfinyl-benzimidazoles, such as omeprazole, andstructurally related compounds, including esomeprazole, lansoprazole,pantoprazole, and rabeprazole, and analogues or derivatives thereof, forexample, omeprazole sulfide, pantoprazole sulfide, lansoprazole sulfide,pantoprazole sodium salt, and the like, and imidazopyridines, such asSCH-28080 and structurally related compounds, could be of value forevening skin tone. An ideal compound for this purpose should be readilydeliverable into the skin, stable, have a therapeutic index of IC₅₀<LD₅₀by a factor of 1,000, and demonstrate long-lasting results.

The PPIs were initially discovered by the inventors to be modulators ofmelanin synthesis during a high throughput screening of indoles andimidazoles. B16F10 melanoma cells were incubated for three days withtest compounds at various concentrations. The cells were fixed, driedand solubilized, and the melanin content was determined. Based on themelanin content of the cells, it was observed that one of the compoundsmost potent in reducing melanin in the cells was omeprazole. It was thendetermined that omeprazole inhibits melanin synthesis withoutcytotoxicity in B16F10 melanoma cells, normal human melanocytes and 3-Dskin (NHEK and melanocytes). Further experiments using Black, Asian andCaucasian melanocytes showed that omeprazole at 12.5, 25 and 50 μg/mlreduced melanin production by about 50%, 30%, and 20%, respectively.

Additionally, the present inventors have observed that omeprazolecreates a more acidic environment in melanocytes. The protocol to detectchanges in pH followed that of Cheli, Y. et al. B16F10 melanoma cellswere seeded in glass bottom dishes and maintained in DMEM medium with10% FBS. Test compounds, omeprazole or forskolin (which creates a morealkaline environment and induces melanin production) were added 18 hoursafter seeding and changes in pH were assessed after either 4 or 24hours. Cells were washed with fresh culture medium and incubated for 20minutes in the presence of 30 μM DAMP ([3-(2,4-dinitroanilino)3′amino-N-methyldipropylamine], a weak base which accumulates in acidiccompartments). Cells were fixed in 3% PFA for 20 minutes at roomtemperature. The glass bottom dishes were washed with PBS, incubated 10minutes in NH₄Cl/PBS at room temperature and permeabilized in PBS with0.1% Triton-100 for two minutes on ice. The dishes were then incubatedwith a green reflecting fluoroscein isothiocyanate (FITC)-labeled rabbitanti-dinitrophenyl (DNP) antibody ( 1/50 PBS plus 1% BSA) for one hoursat 37° C. The intensity of fluorescence indicated the accumulation ofDAMP. Increased intensity of the fluorescence can be related to loweredpH. (Cheli, Y., Luciani, F., Khaled, M., Beuret, L., Billie, K., Gounon,Pl, Ortonne, J. P., Bertolotto, C., and Ballotti, R. Alpha-MSH andcyclic-AMP elevating agents control melanosome pH through aPKA-independent mechanism. J. Biol. Chem., 284:18699-18706, 2009). Thedata are shown in Table I below.

TABLE I EFFECT OF OMEPRAZOLE ON THE PH OF MELANOCYTES Averagefluorescence Conditions per cell ± S.D. 24 hour incubation Control 110.3± 8   Omeprazole 50 μM 139.3 ± 14.4 Forskolin 20 μM   87 ± 15.1 4 hourincubation Control  72.5 ± 31.3 Omeprazole 50 μM 145.5 ± 14.5 4 hourincubation Control  89 ± 23 Omeprazole 25 μM 124.3 ± 2.5  Omeprazole 50μM 133.7 ± 13.3

Fluorescence intensity increased after exposure of cells for 24 hours toomeprazole, indicating that a more acidic pH was induced. On the otherhand, treatment with forskolin decreased DAMP labeling. It has beenpreviously shown that forskolin induces an alkalinization of themelanosome milieu. Additionally, the data show that the acidificationoccurs relatively rapidly, as the intensity of fluorescence issignificantly increased after only 4 hours. Concentrations of 25 μM and50 μM omeprazole are both effective at lowering the pH of melanoma cellsafter 4 hours of treatment. This shorter time period would be expectedif omeprazole acted through direct inhibition of a proton pump ratherthan through some indirect effect requiring, for example, proteinsynthesis of the pump enzyme.

A further unexpected discovery by the inventors was that the compoundSCH-28080 inhibited melanogensis in a manner equally as efficient asomeprazole. SCH-28080, [2-methyl-8-(phenylmethoxy) imidazo (1,2a)pyridine-3-acetonitrile], having the formula shown below, is ahydrophobic amine in the class of imidazopyridine derivatives, morespecifically, substituted pyridyl 1 [1,2-a]imidazoles, a class whichalso includes SCH-32651,[3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine HCl]. SCH-28080is similar to omeprazole in that it is a proton pump inhibitor, but itis distinct from omeprazole and its derivatives in chemical structure,particularly in that it completely lacks a sulfur moiety. Its effects onthe gastric H⁺, K⁺-ATPase are also completely different. SCH28080 is acompetitive inhibitor of the K⁺ binding site and therefore itsinhibition is reversible (Wallmark B., C. Briving, J. Fryklund, K.Munson, R. Jackson, J. Mendlein, E. Rabon, G. Sachs, Inhibition ofGastric H⁺,K⁺-ATPase and Acid Secretion by SCH28080, a SubstitutedPyridyl 1(1,2 α)imidazole. J. Biol. Chem. 262:2077-2084, 1987; Beil, etal., W., Hatchbarth, I, Sewing, K. F.: Mechanism of GastricAntisecretory Effect of SCH 28080, Br. J. Pharmac. 88:19-23, 1986),while omeprazole makes a covalent, irreversible bond. The target site isalso different. SCH-28080 targets the glutamine at position 822 of thegastric pump (Asano S., S. Matsuda, Y. Tega, K. Shimizu, S. Sakamoto, N.Takeguchi, Mutational Analysis of Putative SCH28080 Binding Sites of theGastric H⁺,K⁺-ATPase, J. Biol. Chem. 272, 17668-17674, 1997) whileomeprazole reacts with cysteines at other positions in the protein.

Other compounds in the class of imidazopyridine derivatives include, butare not limited to, soraprazan[(7R,8R,9R)-2,3-dimethyl-8-hydroxy-7(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1,2-h][1,7]-naphthyridine],pumaprazole8-(2-methoxycarbonylamino-6-benzulamino)-2,3-dimethylimidazo-[1,2-a)pyridine-D,L-hemimalate,AR-H047108,(8-[(2-ethyl-6-methylbenzyl)amino]2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamnide;dapiprazole,3-{2-[4-(2-methylphenyl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,5-a]pyridine;AZD0865,((8-[2,6-dimethylbenzyl)amino]-N-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide;and tenatoprazole,3-methoxy-8-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methylsulfinyl]-2,7,9-triazabicyclo[4.3.0]nona-2,4,8,10-tetraene.It is of interest to note that tenatoprazole, shown below, contains asulfinyl moiety and is therefore also structurally related to thesubstituted benzimidazoles. Its inhibition is resistant to reversal.

Acyl quinoline derivatives include, but are not limited to, thecompounds aripiprazole,7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-oneand revaprazan,[5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl-pyrimidine],shown below.

Pyrrolopyridazine derivatives include, but are not limited to, CS-526,7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine,shown below.

Despite these differences, there are clear similarities among thereversible and irreversible proton pump inhibitors that highlight theinvention. First, they are weak bases, which would lead to theiraccumulation at sites of relative acidity. Second, they react with theacidic side of the H⁺, K⁺-ATPase, which in the case of the gastric pumpis in the lumen of the stomach. Third, they are effective inhibitors ofonly the Type I H⁺, K+-ATPases, which are all resistant to ouabain, andwhich are distinct from Type III H⁺, K⁺-ATPases, such as ATP12A found inbladder and colon, which are sensitive to ouabain, resistant toSCH-28080 and which have an aspartic acid residue at the positioncorresponding to the glutamine residue in the Type I H⁺, K⁺-ATPases.

Because both omeprazole (and its analogues and structurally relatedcompounds) and SCH-28080 inhibit melanogenesis despite their differencesin structure and mechanisms of action, this leads to the novelgeneralization that inhibitors of Type I H⁺, K⁺-ATPases are alsoinhibitors of melanogenesis.

The invention is described hereinbelow in greater detail with referenceto its preferred embodiments. These embodiments, however, are set forthto illustrate the invention and are not to be construed as a limitationthereof, the invention being defined by the claims.

In one aspect, the invention relates to a composition for topicalapplication to skin, comprising a skin-lightening/depigmenting effectiveamount of at least one compound or derivative thereof which is aninhibitor of Type I H+, K+-ATPases.

In one preferred embodiment of the first aspect, the invention relatesto a composition for topical application to skin, comprising askin-lightening/depigmenting effective amount of at least one compoundrepresented by the structural formula:

wherein:

R₁ and R₂ are same or different and are each selected from the groupconsisting of hydrogen, alkyl, carbomethoxy, carboethoxy, alkoxy, andalkanoyl, any of which may be halogen-substituted and halogen;

R₆ is selected from the group consisting of hydrogen, methyl, and ethyl;and

R₃, R₄ and R₅ are the same or different and are each selected from thegroup consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy,ethoxyethoxy, propoxy, propoxymethoxy, and the like, any of which may behalogen-substituted;

or a derivative or physiologically acceptable salt, solvate orbioprecursor, or stereoisomer or enantiomer thereof;

formulated into a topically applicable, cosmetically or dermatologicallyacceptable vehicle, carrier or diluent therefor.

Alkyl R₁ and R₂ of formula I are suitably alkyl having up to 7 carbonatoms, preferably up to 4 carbon atoms. Thus, alkyl R may be methyl,ethyl, n-propyl, isopropyl, n-butyl or isobutyl, whether or nothalogen-substituted.

Halogen R₁ and R₂ are chloro, bromo, fluoro, or iodo.

Alkoxy R₁ and R₂ are suitably alkoxy groups having up to 5 carbon atoms,preferably up to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy, orisopropoxy, whether or not halogen-substituted.

Alkanoyl R₁ and R₂ have preferably up to 4 carbon atoms and are e.g.formyl, acetyl, or propionyl, preferably, acetyl, whether or nothalogen-substituted.

One preferred group of compounds of the general formula I are thosewherein R₁ and R₂ are the same or different and are each selected fromthe group consisting of hydrogen, alkyl, and alkoxy, whether or nothalogen-substituted, R₆ is selected from the group consisting ofhydrogen, methyl, and ethyl, and R₃, R₄, and R₅ are the same ordifferent and are each selected from the group consisting of hydrogen,alkyl and alkoxy, whether or not substituted by halogen.

A second preferred group of compounds of the general formula I are thosewherein R₁ and R₂ are the same or different and are each selected fromthe group consisting of hydrogen, methyl, methyl substituted by halogen,methoxy, and methoxy substituted by halogen, R₆ is hydrogen, R₃, R₄, andR₅ are the same or different and are each selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy,methoxymethoxy, ethoxyethoxy, propoxypropoxy, methoxyethoxy,ethoxymethoxy, methoxypropoxy, propoxymethoxy, ethoxypropoxy,propoxyethoxy, whether or not substituted by halogen.

Non-limiting examples of preferred compounds are those in which R1 andR2 are each hydrogen or methoxy, R3 and R5 are methyl and R4 is methoxy;in which R₁, R₂, R₅ and R₆ are hydrogen, R₃ is methyl and R₄ ispropoxymethoxy; in which R₁, R₂, R₃, R₄, R₅ and R₆ all are hydrogen; inwhich R₁, R₂, R₅ and R₆ all are hydrogen, R₃ is methyl and R₄ is ethoxysubstituted by halogen; and in which R₁ and R₂ are hydrogen or methoxysubstituted by halogen, R₆ is hydrogen, R₃ is hydrogen and R₄ and R₅ aremethoxy.

Most preferred for use in the compositions of the present invention areomeprazole, its derivatives and analogues.

A further preferred embodiment of the first aspect of the presentinvention relates to a composition for topical application to skin,comprising a skin-lightening/depigmenting effective amount of at leastone compound represented by the structural formula:

wherein:

R₂ is hydrogen, lower alkyl or hydroxy lower alkyl;

R₃ is lower alkyl, —CH₂CN, hydroxy lower alkyl, —NO, —CH₂N═C or

(wherein R₆ and R₇ are independently selected from the group consistingof hydrogen and lower alkyl) or hydrogen provided R₂ is not hydrogen;

R₄ is Z-T-W wherein Z represents —O—, —NH— or a single bond; Trepresents a straight- or branched-chain lower-alkylene group; when Z isa single bond, T also represents an ethenylene or a propenylene groupwherein the unsaturated carbon is at the single bond; when Z is —O—, Talso represents an allylene group wherein the saturated carbon is at theoxygen; and W represents hydrogen, when T is allylene and Z is —O—, andAr, wherein Ar is selected from thienyl, pyridinyl, furanyl, phenyl andsubstituted phenyl wherein there are one or more substituents on thephenyl independently selected from halogen or lower alkyl; and

R₅ is hydrogen, halogen or lower alkyl;

or a derivative or physiologically acceptable salt, solvate orbioprecursor, or stereoisomer or enantiomer thereof;

formulated into a topically applicable, cosmetically or dermatologicallyacceptable vehicle, carrier or diluent therefor.

As employed throughout this specification, the term “halogen” meansfluoro, chloro, bromo and iodo, with chloro and fluoro being preferred.The term “lower” as it modifies such radicals as alkyl means straight-or branched-chain radicals having up to six carbon atoms, e.g., methyl,ethyl, propyl, butyl, t-butyl, isopropyl, neopentyl, dimethylbutyl andthe like. Methyl is the preferred lower alkyl.

“Pyridinyl” means the 2-, 3- and 4-isomers and their halogen- and loweralkyl-substituted analogs; “thienyl” means the 2- and 3-isomers andtheir halogen- and lower alkyl-substituted analogs; “furanyl” means the2- and 3-isomers and their halogen- and lower alkyl-substituted analogs;

When “Ar” is phenyl, the substituents can be in the meta, ortho and/orpara positions of the phenyl. The preferred substituents are halogen.

The R₅ substituents can be on one or more of the 5-, 6-, 7- or8-positions of the imidazo[1,2-a]pyridine nucleus not alreadysubstituted by an R₄ substituent.

“Pharmaceutically acceptable salts” means salts wherein an acidichydrogen forms an acid addition salt with an amine, e.g., the phosphatesalt of 3-amino-2-methyl-8-phenylmethoxyimidazo-[1,2-a]pyridine.Suitable acids for the pharmaceutically acceptable acid addition saltsinclude hydrochloric, sulfuric, phosphoric, nitric, acetic, propionic,maleic, ascorbic, citric and the like. The salts are prepared byprocedures well known in the art.

A preferred subgroup of compounds of formula II are those wherein R₂represents methyl or ethyl; R₃ represents —NH₂, —NHC₂H₅, —CH₂CN, —CH₃,—CH₂OH or —CH₂N═C; R4 represents —OCH₂Ar, —NHCH₂Ar, —CH═CH—(CH₂)_(n) Aror —CH₂CH₂(CH₂)_(n)Ar wherein n is zero or one and Ar is as definedhereinabove; and R₅ is hydrogen, fluoro, chloro or methyl.

A further preferred subgroup are those compounds in which R₄ is at the8-position and R₅, when other than hydrogen, is at the 7-position.

A still further preferred subgroup are those compounds in which R₄ is atthe 8-position and is selected from phenylmethoxy, phenylethyl,3-phenyl-1-propenyl, phenylethenyl, benzylamino, 3-thienylmethoxy and3-thienylmethansmino; R₂ is methyl; R₃ is amino, cyanomethyl or methyl;and R₅ is hydrogen or methyl at the 7-position.

Non-limiting examples of imidazo[1,2-a]pyridine compounds within thescope of this invention are:

-   1. 3-amino-2-methyl-8-(2-phenylethyl)imidazo-[1,2-a]pyridine;-   2. 2,3-dimethyl-8-[(2-phenyl)ethenyl]imidazo[1,2-a]pyridine;-   3.    3-cyanomethyl-2-methyl-8-(3-phenyl-1-propenyl)imidazo[1,2-a]pyridine;-   4.    2,7-dimethyl-8-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   5. 3-ethylamino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   6. 3-ethylamino-2-methyl-8-(2-phenylethyl)-imidazo[1,2-a]pyridine;-   7. 3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   8. 3-amino-2-ethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   9. 3-amino-2,6-dimethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   10. 3-amino-2,7-dimethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   11.    3-amino-8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   12.    3-amino-8-(4-chlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   13.    3-amino-2-methyl-8-[(3-thienylethyl)amino]imidazo[1,2-a]pyridine;-   14. 3-amino-2-methyl-8-(3-thienylmethoxy)imidazo[1,2-a]pyridine;-   15. 3-amino-2-methyl-8-(2-thienylmethoxy)imidazo[1,2-a]pyridine;-   16. 2-methyl-3-isocyanomethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   17.    2-methyl-8-[3-thienylmethylamino]-imidazo[1,2-a]pyridine-3-acetonitrile;-   18.    2-methyl-6-(2-phenylethyl)-imidazo[1,2-a]pyridine-3-acetonitrile;-   19. 3-amino-2-methyl-6-(2-phenylethyl)-imidazo[1,2-a]pyridine;-   20.    3-amino-8-(4-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   21. 2-methyl-8-(2,4,6-trimethylphenylmethoxy)imidazo[1,2-a]pyridine;-   22. 8-(3,4-dichlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   23.    8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   24. 8-(4-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   25. 2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine;-   26. 8-(4-chlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   27.    2-methyl-8-(2-thienylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;-   28.    2-methyl-8-(2-pyridylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;-   29.    8-(3,4-dichlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   30.    8-(4-methoxyphenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   31.    8-(4-t-butylphenylmethoxy-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   32.    8-(4-chlorophenylmethoxy)-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   33.    8-(3,4-dichlorophenylmethoxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;-   34.    8-(4-chlorophenylmethoxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;-   35. 8-phenylmethoxy-2-ethylimidazo[1,2-a]pyridine;-   36. 8-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   37. 8-phenylmethoxy-2-hydroxymethylimidazo[1,2-a]pyridine;-   38.    3-hydroxymethyl-2-methyl-8-(2-phenylethoxy)imidazo[1,2-a]pyridine;-   39. 8-phenylmethoxy-2,3-dimethylimidazo[1,2-a]pyridine;-   40.    2-methyl-8-(2-phenylethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;-   41.    2-methyl-8-(1-phenylethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;-   42. 2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine-3-acetonitrile;-   43.    3-hydroxymethyl-2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine;-   44.    2-methyl-8-(3-phenylpropoxyl)imidazo[1,2-a]pyridine-3-acetonitrile;-   45.    8-phenylmethoxy-2-isopropylimidazo[1,2-a]pyridine-3-acetonitrile;-   46. 8-phenylmethoxy-2-ethylimidazo[1,2-a]pyridine-3-acetonitrile;-   47. 8-benzylamino-2,3-dimethylimidazo[1,2-a]pyridine;-   48. 8-phenylmethoxy-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   49. 8-phenylmethoxy-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;-   50.    3-hydroxymethyl-8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   51.    8-(4-t-butylbenzyloxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;-   52.    8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   53.    8-(4-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   54.    2-methyl-8-(2,4,6-trimethylphenylmethoxy)imidazo[1,2-a]pyridine-2-acetonitrile;-   55. 8-benzylamino-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   56.    2-methyl-8-(3-thienylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;-   57. 2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   58. 8-allyloxy-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   59. 2-ethyl-8-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   60. 2-ethyl-3-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   61. 3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine and the    phosphate acid addition salt thereof;-   62.    2-methyl-8-(3-phenylpropyl)imidazo[1,2-a]pyridine-3-acetonitrile;-   63. 2-methyl-6-benzylaminoimidazo[1,2-a]pyridine-3-acetonitrile;-   64. 2-methyl-6-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   65. 2-methyl-5-benzylaminoimidazo[1,2-a]pyridine-3-acetonitrile;-   66. 2-methyl-5-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   67. 2,3-dimethyl-5-phenylmethoxyimidazo[1,2-a]pyridine;-   68. 2-methyl-7-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   69. 3-(cyanomethyl)-2-methyl-8-phenylmethoxy-imidazo[1,2-a]pyridine;-   70. 3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine.

Preferred examples include3-(cyanomethyl)-2-methyl-8-phenylmethoxy-imidazo[1,2-a]pyridine (SCH28080) and 3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine (SCH32651).

It is apparent that the compounds of this invention may be named indifferent ways. Thus, “benzyloxy” and “phenylmethoxy” are synonymous asare “cyanomethyl” and “acetonitrile”. Therefore, as used herein, thenames are interchangeable.

In a further aspect, the present invention concerns a method forlightening/depigmenting the skin comprising applying to the skin in needthereof a composition comprising a skin-lightening/depigmentingeffective amount of at least one compound or derivative thereof which isan inhibitor of Type I H+, K+-ATPases.

In a preferred embodiment of this aspect of the present invention, themethod for lightening/depigmenting the skin comprises applying to theskin in need thereof a composition comprising askin-lightening/depigmenting effective amount of at least one compoundor derivative thereof represented by the structural formula:

wherein:

R₁ and R₂ are same or different and are each selected from the groupconsisting of hydrogen, alkyl, carbomethoxy, carboethoxy, alkoxy, andalkanoyl, any of which may be halogen-substituted, and halogen;

R₆ is selected from the group consisting of hydrogen, methyl, and ethyl;and

R₃, R₄ and R₅ are the same or different and are each selected from thegroup consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy,ethoxyethoxy, propoxy, propoxymethoxy, and the like, any of which may behalogen-substituted;

or a derivative or physiologically acceptable salt, solvate orbioprecursor, or stereoisomer or enantiomer thereof;

formulated into a topically applicable, cosmetically or dermatologicallyacceptable vehicle, carrier or diluent therefor.

Alkyl R₁ and R₂ of formula I are suitably alkyl having up to 7 carbonatoms, preferably up to 4 carbon atoms. Thus, alkyl R may be methyl,ethyl, n-propyl, isopropyl, n-butyl or isobutyl, whether or nothalogen-substituted.

Halogen R₁ and R₂ are chloro, bromo, fluoro, or iodo.

Alkoxy R₁ and R₂ are suitably alkoxy groups having up to 5 carbon atoms,preferably up to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy, orisopropoxy, including halogen-substituted groups.

Alkanoyl R₁ and R₂ have preferably up to 4 carbon atoms and are e.g.formyl, acetyl, or propionyl, preferably acetyl, includinghalogen-substituted groups.

One preferred group of compounds of the general formula I for use inthis method of the present invention are those wherein R₁ and R₂ are thesame or different and are each selected from the group consisting ofhydrogen, alkyl, and alkoxy, whether or not halogen-substituted, R₆ isselected from the group consisting of hydrogen, methyl, and ethyl, andR₃, R₄, and R₅ are the same or different and are each selected from thegroup consisting of hydrogen, alkyl and alkoxy, whether or notsubstituted by halogen.

A second preferred group of compounds of the general formula I are thosewherein R₁ and R₂ are the same or different and are each selected fromthe group consisting of hydrogen, methyl, methyl substituted by halogen,methoxy, and methoxy substituted by halogen, R₆ is hydrogen, R₃, R₄, andR₅ are the same or different and are each selected from the groupconsisting of hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy,methoxymethoxy, ethoxyethoxy, propoxypropoxy, methoxyethoxy,ethoxymethoxy, methoxypropoxy, propoxymethoxy, ethoxypropoxy,propoxyethoxy, whether or not substituted by halogen.

Non-limiting examples of preferred compounds are those in which R1 andR2 are each hydrogen or methoxy, R3 and R5 are methyl and R4 is methoxy;in which R₁, R₂, R₅ and R₆ are hydrogen, R₃ is methyl and R₄ ispropoxymethoxy; in which R₁, R₂, R₃, R₁, R₅ and R₆ all are hydrogen; inwhich R₁, R₂, R₅ and R₆ all are hydrogen, R₃ is methyl and R₄ is ethoxysubstituted by halogen; and in which R₁ and R₂ are hydrogen or methoxysubstituted by halogen, R₆ is hydrogen, R₃ is hydrogen and R₁ and R₅ aremethoxy.

Most preferred for use in the methods of the present invention areomeprazole, its derivatives and analogues.

In a further preferred embodiment of this aspect of the presentinvention, the method for lightening/depigmenting the skin comprisesapplying to the skin in need thereof a composition comprising a skinlightening/depigmenting effective amount of at least one compound orderivative thereof represented by the structural formula:

wherein:

R₂ is hydrogen, lower alkyl or hydroxy lower alkyl;

R₃ is lower alkyl, —CH₂CN, hydroxy lower alkyl, —NO, —CH₂N═C or

(wherein R₆ and R₇ are independently selected from the group consistingof hydrogen and lower alkyl) or hydrogen provided R₂ is not hydrogen; R4is Z-T-W wherein Z represents —O—, —NH— or a single bond; T represents astraight- or branched-chain lower-alkylene group; when Z is a singlebond, T also represents an ethenylene or a propenylene group wherein theunsaturated carbon is at the single bond; when Z is —O—, T alsorepresents an allylene group wherein the saturated carbon is at theoxygen; and W represents hydrogen, when T is allylene and Z is —O—, andAr, wherein Ar is selected from thienyl, pyridinyl, furanyl, phenyl andsubstituted phenyl wherein there are one or more substituents on thephenyl independently selected from halogen or lower alkyl; and R₅ ishydrogen, halogen or lower alkyl;

or a derivative or physiologically acceptable salt, solvate orbioprecursor, or stereoisomer or enantiomer thereof;

formulated into a topically applicable, cosmetically or dermatologicallyacceptable vehicle, carrier or diluent therefor.

A preferred subgroup of compounds of Formula II for use in this methodare those wherein R₂ represents methyl or ethyl; R₃ represents —NH₂,—NHC₂H3, —CH₂CN, —CH₃, —CH₂OH or —CH₂N═C; R4 represents —OCH₂Ar,—NHCH₂Ar, —CH═CH—(CH₂)_(n) Ar or —CH₂CH₂(CH₂)_(n)Ar wherein n is zero orone and Ar is as defined hereinabove; and R₅ is hydrogen, fluoro, chloroor methyl.

A further preferred subgroup of compounds in wherein R₄ is at the8-position and R₅, when other than hydrogen, is at the 7-position.

A still further preferred subgroup are those compounds in which R₄ is atthe 8-position and is selected from phenylmethoxy, phenylethyl,3-phenyl-1-propenyl, phenylethenyl, benzylamino, 3-thienylmethoxy and3-thienylmethanamino; R₂ is methyl; R₃ is amino, cyanomethyl or methyl;and R₅ is hydrogen or methyl at the 7-position.

Non-limiting examples of imidazo[1,2-a]pyridine compounds within thescope of this invention are:

-   1. 3-amino-2-methyl-8-(2-phenylethyl)imidazo-[1,2-a]pyridine;-   2. 2,3-dimethyl-8-[(2-phenyl)ethenyl]imidazo[1,2-a]pyridine;-   3.    3-cyanomethyl-2-methyl-8-(3-phenyl-1-propenyl)imidazo[1,2-a]pyridine;-   4.    2,7-dimethyl-8-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   5. 3-ethylamino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   6. 3-ethylamino-2-methyl-8-(2-phenylethyl)-imidazo[1,2-a]pyridine;-   7. 3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   8. 3-amino-2-ethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   9. 3-amino-2,6-dimethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   10. 3-amino-2,7-dimethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   11.    3-amino-8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   12.    3-amino-8-(4-chlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   13.    3-amino-2-methyl-8-[(3-thienylethyl)amino]imidazo[1,2-a]pyridine;-   14. 3-amino-2-methyl-8-(3-thienylmethoxy)imidazo[1,2-a]pyridine;-   15. 3-amino-2-methyl-8-(2-thienylmethoxy)imidazo[1,2-a]pyridine;-   16. 2-methyl-3-isocyanomethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   17.    2-methyl-8-[3-thienylmethylamino]-imidazo[1,2-a]pyridine-3-acetonitrile;-   18.    2-methyl-6-(2-phenylethyl)-imidazo[1,2-a]pyridine-3-acetonitrile;-   19. 3-amino-2-methyl-6-(2-phenylethyl)-imidazo[1,2-a]pyridine;-   20.    3-amino-8-(4-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   21. 2-methyl-8-(2,4,6-trimethylphenylmethoxy)imidazo[1,2-a]pyridine;-   22. 8-(3,4-dichlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   23.    8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   24. 8-(4-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   25. 2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine;-   26. 8-(4-chlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   27.    2-methyl-8-(2-thienylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;-   28.    2-methyl-8-(2-pyridylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;-   29.    8-(3,4-dichlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   30.    8-(4-methoxyphenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   31.    8-(4-t-butylphenylmethoxy-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   32.    8-(4-chlorophenylmethoxy)-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   33.    8-(3,4-dichlorophenylmethoxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;-   34.    8-(4-chlorophenylmethoxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;-   35. 8-phenylmethoxy-2-ethylimidazo[1,2-a]pyridine;-   36. 8-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   37. 8-phenylmethoxy-2-hydroxymethylimidazo[1,2-a]pyridine;-   38.    3-hydroxymethyl-2-methyl-8-(2-phenylethoxy)imidazo[1,2-a]pyridine;-   39. 8-phenylmethoxy-2,3-dimethylimidazo[1,2-a]pyridine;-   40.    2-methyl-8-(2-phenylethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;-   41.    2-methyl-8-(1-phenylethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;-   42. 2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine-3-acetonitrile;-   43.    3-hydroxymethyl-2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine;-   44.    2-methyl-8-(3-phenylpropoxyl)imidazo[1,2-a]pyridine-3-acetonitrile;-   45.    8-phenylmethoxy-2-isopropylimidazo[1,2-a]pyridine-3-acetonitrile;-   46. 8-phenylmethoxy-2-ethylimidazo[1,2-a]pyridine-3-acetonitrile;-   47. 8-benzylamino-2,3-dimethylimidazo[1,2-a]pyridine;-   48. 8-phenylmethoxy-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   49. 8-phenylmethoxy-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;-   50.    3-hydroxymethyl-8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;-   51.    8-(4-t-butylbenzyloxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;-   52.    8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   53.    8-(4-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   54.    2-methyl-8-(2,4,6-trimethylphenylmethoxy)imidazo[1,2-a]pyridine-2-acetonitrile;-   55. 8-benzylamino-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   56.    2-methyl-8-(3-thienylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;-   57. 2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   58. 8-allyloxy-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;-   59. 2-ethyl-8-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   60. 2-ethyl-3-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;-   61. 3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine and the    phosphate acid addition salt thereof;-   62.    2-methyl-8-(3-phenylpropyl)imidazo[1,2-a]pyridine-3-acetonitrile;-   63. 2-methyl-6-benzylaminoimidazo[1,2-a]pyridine-3-acetonitrile;-   64. 2-methyl-6-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   65. 2-methyl-5-benzylaminoimidazo[1,2-a]pyridine-3-acetonitrile;-   66. 2-methyl-5-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   67. 2,3-dimethyl-5-phenylmethoxyimidazo[1,2-a]pyridine;-   68. 2-methyl-7-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;-   69. 3-(cyanomethyl)-2-methyl-8-phenylmethoxy-imidazo[1,2-a]pyridine;-   70. 3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine.

Preferred examples of compounds useful in this method of the presentinvention include3-(cyanomethyl)-2-methyl-8-phenylmethoxy-imidazo[1,2-a]pyridine (SCH28080) and 3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine (SCH32651).

A further aspect of the present invention concerns a method of screeningcompounds for efficacy in modulating melanin synthesis. In oneembodiment of this aspect of the invention, the compounds are screenedfor efficacy in decreasing the amount of melanin in cells, the methodcomprising (a) selecting a compound to be tested; (b) incubatingmelanocytes or melanoma cells with the test compound at variousconcentrations and with a positive control compound; and (c) determiningmelanin content. In a further embodiment of this aspect of theinvention, the compounds are screened for efficacy in lowering the pH ofcells, the method comprising (a) selecting a compound to be tested; (b)incubating melanocytes or melanoma cells with the test compound atvarious concentrations and with a positive control compound; (c)incubating the melanocytes or melanoma cells with a weak base, such as30 μM DAMP; (d) incubating the cells with a labelled antibody to theweak base, such as fluorescent FITC-labeled rabbit anti-DNP antibody;and (e) assessing the change in pH, such as by observing the amount offluorescence produced.

The inhibitors of Type I H⁺, K⁺-ATPases may be used in a pharmaceuticalproduct or a cosmetic or dermatological product. Skin compositions ofthe invention may comprise from about 0.00005% to about 0.5% of theactive compound by weight of the total composition, more preferably fromabout 0.0005% to about 0.05%, more preferably still from about 0.005% toabout 0.01%, such as about 0.0035%.

Cosmetic or dermatological compositions of the present inventions my befound in a variety of forms, such as anhydrous compositions,aqueous-based solutions, serums, gels, creams, lotions, mousses, sticks,sprays, ointments, essences, pastes, microcapsules, or color cosmeticcompositions such as foundation, blush, eyeshadow, and the like. Theymay contain many other additional cosmetically and/or dermatologicallyacceptable ingredients, such as additional skin lightening agents ortyrosinase inhibitors, antioxidants, anti-inflammatory agents,botanicals, humectants, moisturizers, sunscreens, preservatives,colorants, perfumes, and the like. In the case where the composition isin the anhydrous form the Type I H+, K+-ATPase inhibitor compound orderivative thereof may be solubilized or dispersed in the oil phase ofthe emulsion; or if the Type I H⁺, K⁺-ATPase inhibitor compound orderivative thereof is water soluble it may be solvated in polarsolvents, typically ingredients referred to as humectants such asglycerine or alkylene glycols prior to formation of an anhydrousemulsion. If the composition is in the emulsion form, the Type I H⁺,K⁺-ATPase inhibitor compound or derivative thereof may be found in thewater phase or the oil phase of the emulsion depending on the type ofderivative. For example, certain hydrophilic derivatives which are watersoluble will generally be solubilized in the water phase of theemulsion. Certain other derivatives which are lipophilic in nature willmore likely be found in the oil phase of the emulsion.

Suitable serums or gels will generally comprise from about 1-99% water,and optionally from about 0.001-30% of an aqueous phase thickeningagent. The other ingredients mentioned herein may be present in thepercentage ranges set forth.

Typical skin creams or lotions comprise from about 5-98% water, 1-85%oil, and from about 0.1 to 20% of one or more surfactants. Preferablythe surfactants are nonionic and may be in the form of silicones ororganic nonionic surfactants.

Typical color cosmetic compositions such as foundations, blush,eyeshadow, and the like, will preferably contain from about 5-98% water,1-85% oil, and from about 0.1 to 20% of one or more surfactants inaddition to from about 0.1 to 65% of particulates that are pigments or acombination of pigments and powders.

In the case where the compositions are in the form of aqueous solutions,dispersions or emulsions, in addition to water the aqueous phase maycontain one or more aqueous phase structuring agents, that is, an agentthat increases the viscosity or thickens, the aqueous phase of thecomposition. This is particularly desirable when the composition is inthe form of a serum or gel. The aqueous phase structuring agent shouldbe compatible with the Type I H⁺, K⁺-ATPase inhibitor compound orderivative thereof, particularly if the particular Type I H⁺, K⁺-ATPaseinhibitor compound or derivative thereof is water soluble, and alsocompatible with the other ingredients in the formulation. Suitableranges of aqueous phase structuring agent, if present, are from about0.01 to 30%, preferably from about 0.1 to 20%, more preferably fromabout 0.5 to 15% by weight of the total composition. Examples of suchagents include various acrylate based thickening agents, natural orsynthetic gums, polysaccharides, and the like, including but not limitedto those set forth below. When the Type I H⁺, K⁺-ATPase inhibitorcompound or derivative thereof is in the water soluble form, the aqueousphase thickening agent also contributes to stabilizing this ingredientin the composition and improving penetration into the stratum corneum.Such structuring agents may include the following:

A. Polysaccharides

Polysaccharides may be suitable aqueous phase thickening agents.Examples of such polysaccharides include naturally derived materialssuch as agar, agarose, alicaligenes polysaccharides, algin, alginicacid, acacia gum, amylopectin, chitin, dextran, cassia gum, cellulosegum, gelatin, gellan gum, hyaluronic acid, hydroxyethyl cellulose,methyl cellulose, ethyl cellulose, pectin, sclerotium gum, xanthan gum,pectin, trehelose, gelatin, and so on.

B. Acrylate Polymers

Also suitable are different types of synthetic polymeric thickeners. Onetype includes acrylic polymeric thickeners comprised of monomers A and Bwherein A is selected from the group consisting of acrylic acid,methacrylic acid, and mixtures thereof; and B is selected from the groupconsisting of a C₁₋₂₂ alkyl acrylate, a C₁₋₂₂ alkyl methacrylate, andmixtures thereof are suitable. In one embodiment the A monomer comprisesone or more of acrylic acid or methacrylic acid, and the B monomer isselected from the group consisting of a C₁₋₁₀, most preferably C₁₋₄alkyl acrylate, a C₁₋₁₀, most preferably C₁₋₄ alkyl methacrylate, andmixtures thereof. Most preferably the B monomer is one or more of methylor ethyl acrylate or methacrylate. The acrylic copolymer may be suppliedin an aqueous solution having a solids content ranging from about10-60%, preferably 20-50%, more preferably 25-45% by weight of thepolymer, with the remainder water. The composition of the acryliccopolymer may contain from about 0.1-99 parts of the A monomer, andabout 0.1-99 parts of the B monomer. Acrylic polymer solutions includethose sold by Seppic, Inc., under the tradename Capigel.

Also suitable are acrylic polymeric thickeners that are copolymer of A,B, and C monomers wherein A and B are as defined above, and C has thegeneral formula:

wherein Z is —(CH₂)_(m); wherein m is 1-10, n is 2-3, o is 2-200, and Ris a C₁₀₋₃₀ straight or branched chain alkyl. Examples of the secondarythickening agent above, are copolymers where A and B are defined asabove, and C is CO, and wherein n, o, and R are as above defined.Examples of such secondary thickening agents includeacrylates/steareth-20 methacrylate copolymer, which is sold by Rohm &Haas under the tradename Acrysol ICS-1.

Also suitable are acrylate based anionic amphiphilic polymers containingat least one hydrophilic unit and at least one allyl ether unitcontaining a fatty chain. Preferred are those where the hydrophilic unitcontains an ethylenically unsaturated anionic monomer, more specificallya vinyl carboxylic acid such as acrylic acid, methacrylic acid ormixtures thereof, and where the allyl ether unit containing a fattychain corresponds to the monomer of the formula:

CH₂═CR′CH₂OB_(n)R

in which R′ denotes H or CH₃, B denotes the ethylenoxy radical, n iszero or an integer ranging from 1 to 100, R denotes a hydrocarbonradical selected from alkyl, arylalkyl, aryl, alkylaryl and cycloalkylradicals which contain from 8 to 30 carbon atoms, preferably from 10 to24, and even more particularly from 12 to 18 carbon atoms. Morepreferred in this case is where R′ denotes H, n is equal to 10 and Rdenotes a stearyl (C18) radical. Anionic amphiphilic polymers of thistype are described and prepared in U.S. Pat. Nos. 4,677,152 and4,702,844, both of which are hereby incorporated by reference in theirentirety. Among these anionic amphiphilic polymers, polymers formed of20 to 60% by weight acrylic acid and/or methacrylic acid, of 5 to 60% byweight lower alkyl methacrylates, of 2 to 50% by weight allyl ethercontaining a fatty chain as mentioned above, and of 0 to 1% by weight ofa crosslinking agent which is a well-known copolymerizable polyethylenicunsaturated monomer, for instance diallyl phthalate, allyl(meth)acrylate, divinylbenzene, (poly)ethylene glycol dimethacrylate andmethylenebisacrylamide. Commercial examples of such polymers arecrosslinked terpolymers of methacrylic acid, of ethyl acrylate, ofpolyethylene glycol (having 10 EO units) ether of stearyl alcohol orsteareth-10, in particular those sold by the company Allied Colloidsunder the names SALCARE SC80 and SALCARE SC90, which are aqueousemulsions containing 30% of a crosslinked terpolymer of methacrylicacid, of ethyl acrylate and of steareth-10 allyl ether (40/50/10).

Also suitable are acrylate copolymers such as Polyacrylate-3 which is acopolymer of methacrylic acid, methylmethacrylate, methylstyreneisopropylisocyanate, and PEG-40 behenate monomers; Polyacrylate-10 whichis a copolymer of sodium acryloyldimethyltaurate, sodium acrylate,acrylamide and vinyl pyrrolidone monomers; or Polyacrylate-11, which isa copolymer of sodium acryloyldimethylacryloyldimethyl taurate, sodiumacrylate, hydroxyethyl acrylate, lauryl acrylate, butyl acrylate, andacrylamide monomers.

Also suitable are crosslinked acrylate based polymers where one or moreof the acrylic groups may have substituted long chain alkyl (such as6-40, 10-30, and the like) groups, for example acrylates/C₁₀₋₃₀ alkylacrylate crosspolymer which is a copolymer of C10-30 alkyl acrylate andone or more monomers of acrylic acid, methacrylic acid, or one of theirsimple esters crosslinked with the allyl ether of sucrose or the allylether of pentaerythritol. Such polymers are commonly sold under theCarbopol or Pemulen tradenames and have the CTFA name carbomer.

One particularly suitable type of aqueous phase thickening agent areacrylate based polymeric thickeners sold by Clariant under theAristoflex trademark such as Aristoflex AVC, which is ammoniumacryloyldimethyltaurate/VP copolymer; Aristoflex AVL which is the samepolymer as found in AVC dispersed in a mixture containingcaprylic/capric triglyceride, trilaureth-4, and polyglyceryl-2sesquiisostearate; or Aristoflex HMB which is ammoniumacryloyldimethyltaurate/beheneth-25 methacrylate crosspolymer, and thelike.

C. High Molecular Weight PEG or Polyglycerins

Also suitable as the aqueous phase thickening agents are variouspolyethylene glycols (PEG) derivatives where the degree ofpolymerization ranges from 1,000 to 200,000. Such ingredients areindicated by the designation “PEG” followed by the degree ofpolymerization in thousands, such as PEG-45M, which means PEG having45,000 repeating ethylene oxide units. Examples of suitable PEGderivatives include PEG 2M, 5M, 7M, 9M, 14M, 20M, 23M, 25M, 45M, 65M,90M, 115M, 160M, 180M, and the like.

Also suitable are polyglycerins which are repeating glycerin moietieswhere the number of repeating moieties ranges from 15 to 200, preferablyfrom about 20-100. Examples of suitable polyglycerins include thosehaving the CTFA names polyglycerin-20, polyglycerin-40, and the like.

In the event the compositions of the invention are in anhydrous oremulsion form, the composition will comprise an oil phase. Oilyingredients are desirable for the skin moisturizing and protectiveproperties. Suitable oils include silicones, esters, vegetable oils,synthetic oils, including but not limited to those set forth herein. Theoils may be volatile or nonvolatile, and are preferably in the form of apourable liquid at room temperature. The term “volatile” means that theoil has a measurable vapor pressure or a vapor pressure of at leastabout 2 mm. of mercury at 20° C. The term “nonvolatile” means that theoil has a vapor pressure of less than about 2 mm. of mercury at 20° C.Suitable oils may include the following:

A. Volatile Oils

Suitable volatile oils generally have a viscosity ranging from about 0.5to 5 centistokes 25° C. and include linear silicones, cyclic silicones,paraffinic hydrocarbons, or mixtures thereof. Volatile oils may be usedto promote more rapid drying of the skin care composition after it isapplied to skin. Volatile oils are more desirable when the skin careproducts containing the Type I H⁺, K⁺-ATPase inhibitor compound orderivative thereof are being formulated for consumers that havecombination or oily skin. The term “combination” with respect to skintype means skin that is oily in some places on the face (such as theT-zone) and normal in others.

1. Volatile Silicones

Cyclic silicones are one type of volatile silicone that may be used inthe composition. Such silicones have the general formula:

where n=3-6, preferably 4, 5, or 6.

Also suitable are linear volatile silicones, for example, those havingthe general formula:

(CH₃)₃Si—O—[Si(CH₃)₂—O_(n)]—Si(CH₃)₃

where n=0, 1, 2, 3, 4, or 5, preferably 0, 1, 2, 3, or 4.

Cyclic and linear volatile silicones are available from variouscommercial sources including Dow Corning Corporation and GeneralElectric. The Dow Corning linear volatile silicones are sold under thetradenames Dow Corning 244, 245, 344, and 200 fluids. These fluidsinclude hexamethyldisiloxane (viscosity 0.65 centistokes (abbreviatedcst)), octamethyltrisiloxane (1.0 cst), decamethyltetrasiloxane (1.5cst), dodecamethylpentasiloxane (2 cst) and mixtures thereof, with allviscosity measurements being at 25° C.

Suitable branched volatile silicones include alkyl trimethicones such asmethyl trimethicone, a branched volatile silicone having the generalformula:

Methyl trimethicone may be purchased from Shin-Etsu Silicones under thetradename TMF-1.5, having a viscosity of 1.5 centistokes at 25° C.

2. Volatile Paraffinic Hydrocarbons

Also suitable as the volatile oils are various straight or branchedchain paraffinic hydrocarbons having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20 carbon atoms, more preferably 8 to 16 carbonatoms. Suitable hydrocarbons include pentane, hexane, heptane, decane,dodecane, tetradecane, tridecane, and C₈₋₂₀ isoparaffins as disclosed inU.S. Pat. Nos. 3,439,088 and 3,818,105, both of which are herebyincorporated by reference.

Preferred volatile paraffinic hydrocarbons have a molecular weight of70-225, preferably 160 to 190 and a boiling point range of 30 to 320,preferably 60 to 260° C., and a viscosity of less than about 10 cst. at25° C. Such paraffinic hydrocarbons are available from EXXON under theISOPARS trademark, and from the Permethyl Corporation. Suitable C₁₂isoparaffins are manufactured by Permethyl Corporation under thetradename Permethyl 99A. Various C₁₆ isoparaffins commerciallyavailable, such as isohexadecane (having the tradename Permethyl R), arealso suitable.

B. Non-Volatile Oils

A variety of nonvolatile oils are also suitable for use in thecompositions of the invention. The nonvolatile oils generally have aviscosity of greater than about 5 to 10 centistokes at 25° C., and mayrange in viscosity up to about 1,000,000 centipoise at 25° C. Examplesof nonvolatile oils include, but are not limited to:

1. Esters

Suitable esters are mono-, di-, and triesters. The composition maycomprise one or more esters selected from the group, or mixturesthereof.

(a) Monoesters

Monoesters are defined as esters formed by the reaction of amonocarboxylic acid having the formula R—COOH, wherein R is a straightor branched chain saturated or unsaturated alkyl having 2 to 45 carbonatoms, or phenyl; and an alcohol having the formula R—OH wherein R is astraight or branched chain saturated or unsaturated alkyl having 2-30carbon atoms, or phenyl. Both the alcohol and the acid may besubstituted with one or more hydroxyl groups. Either one or both of theacid or alcohol may be a “fatty” acid or alcohol, and may have fromabout 6 to 30 carbon atoms, more preferably 12, 14, 16, 18, or 22 carbonatoms in straight or branched chain, saturated or unsaturated form.Examples of monoester oils that may be used in the compositions of theinvention include hexyl laurate, butyl isostearate, hexadecylisostearate, cetyl palmitate, isostearyl neopentanoate, stearylheptanoate, isostearyl isononanoate, stearyl lactate, stearyl octanoate,stearyl stearate, isononyl isononanoate, and so on.

(b). Diesters

Suitable diesters are the reaction product of a dicarboxylic acid and analiphatic or aromatic alcohol or an aliphatic or aromatic alcohol havingat least two substituted hydroxyl groups and a monocarboxylic acid. Thedicarboxylic acid may contain from 2 to 30 carbon atoms, and may be inthe straight or branched chain, saturated or unsaturated form. Thedicarboxylic acid may be substituted with one or more hydroxyl groups.The aliphatic or aromatic alcohol may also contain 2 to 30 carbon atoms,and may be in the straight or branched chain, saturated, or unsaturatedform. Preferably, one or more of the acid or alcohol is a fatty acid oralcohol, i.e. contains 12-22 carbon atoms. The dicarboxylic acid mayalso be an alpha hydroxy acid. The ester may be in the dimer or trimerform. Examples of diester oils that may be used in the compositions ofthe invention include diisotearyl malate, neopentyl glycol dioctanoate,dibutyl sebacate, dicetearyl dimer dilinoleate, dicetyl adipate,diisocetyl adipate, diisononyl adipate, diisostearyl dimer dilinoleate,diisostearyl fumarate, diisostearyl malate, dioctyl malate, and so on.

(c). Triesters

Suitable triesters comprise the reaction product of a tricarboxylic acidand an aliphatic or aromatic alcohol or alternatively the reactionproduct of an aliphatic or aromatic alcohol having three or moresubstituted hydroxyl groups with a monocarboxylic acid. As with themono- and diesters mentioned above, the acid and alcohol contain 2 to 30carbon atoms, and may be saturated or unsaturated, straight or branchedchain, and may be substituted with one or more hydroxyl groups.Preferably, one or more of the acid or alcohol is a fatty acid oralcohol containing 12 to 22 carbon atoms. Examples of triesters includeesters of arachidonic, citric, or behenic acids, such as triarachidin,tributyl citrate, triisostearyl citrate, tri C₁₂₋₁₃ alkyl citrate,tricaprylin, tricaprylyl citrate, tridecyl behenate, trioctyldodecylcitrate, tridecyl behenate; or tridecyl cocoate, tridecyl isononanoate,and so on.

Esters suitable for use in the composition are further described in theC.T.F.A. Cosmetic Ingredient Dictionary and Handbook, Eleventh Edition,2006, under the classification of “Esters”, the text of which is herebyincorporated by reference in its entirety.

2. Hydrocarbon Oils

It may be desirable to incorporate one or more nonvolatile hydrocarbonoils into the composition. Suitable nonvolatile hydrocarbon oils includeparaffinic hydrocarbons and olefins, preferably those having greaterthan about 20 carbon atoms. Examples of such hydrocarbon oils includeC₂₄₋₂₈ olefins, C₃₀₋₄₅ olefins, C₂₀₋₄₀ isoparaffins, hydrogenatedpolyisobutene, polyisobutene, polydecene, hydrogenated polydecene,mineral oil, pentahydrosqualene, squalene, squalane, and mixturesthereof. In one preferred embodiment such hydrocarbons have a molecularweight ranging from about 300 to 1000 Daltons.

3. Glyceryl Esters of Fatty Acids

Synthetic or naturally occurring glyceryl esters of fatty acids, ortriglycerides, are also suitable for use in the compositions. Bothvegetable and animal sources may be used. Examples of such oils includecastor oil, lanolin oil, C₁₀₋₁₈ triglycerides,caprylic/capric/triglycerides, sweet almond oil, apricot kernel oil,sesame oil, camelina sativa oil, tamanu seed oil, coconut oil, corn oil,cottonseed oil, linseed oil, ink oil, olive oil, palm oil, illipebutter, rapeseed oil, soybean oil, grapeseed oil, sunflower seed oil,walnut oil, and the like.

Also suitable are synthetic or semi-synthetic glyceryl esters, such asfatty acid mono-, di-, and triglycerides which are natural fats or oilsthat have been modified, for example, mono-, di- or triesters of polyolssuch as glycerin. In an example, a fatty (C₁₂₋₂₂) carboxylic acid isreacted with one or more repeating glyceryl groups. glyceryl stearate,diglyceryl diiosostearate, polyglyceryl-3 isostearate, polyglyceryl-4isostearate, polyglyceryl-6 ricinoleate, glyceryl dioleate, glyceryldiisotearate, glyceryl tetraisostearate, glyceryl trioctanoate,diglyceryl distearate, glyceryl linoleate, glyceryl myristate, glycerylisostearate, PEG castor oils, PEG glyceryl oleates, PEG glycerylstearates, PEG glyceryl tallowates, and so on.

4. Nonvolatile Silicones

Nonvolatile silicone oils, both water soluble and water insoluble, arealso suitable for use in the composition. Such silicones preferably havea viscosity ranging from about greater than 5 to 800,000 cst, preferably20 to 200,000 cst at 25° C. Suitable water insoluble silicones includeamine functional silicones such as amodimethicone.

For example, such nonvolatile silicones may have the following generalformula:

wherein R and R′ are each independently C₁₋₃₀ straight or branchedchain, saturated or unsaturated alkyl, phenyl or aryl, trialkylsiloxy,and x and y are each independently 1-1,000,000; with the proviso thatthere is at least one of either x or y, and A is alkyl siloxy endcapunit. Preferred is where A is a methyl siloxy endcap unit; in particulartrimethylsiloxy, and R and R′ are each independently a C₁₋₃₀ straight orbranched chain alkyl, phenyl, or trimethylsiloxy, more preferably aC₁₋₂₂ alkyl, phenyl, or trimethylsiloxy, most preferably methyl, phenyl,or trimethylsiloxy, and resulting silicone is dimethicone, phenyldimethicone, diphenyl dimethicone, phenyl trimethicone, ortrimethylsiloxyphenyl dimethicone. Other examples include alkyldimethicones such as cetyl dimethicone, and the like wherein at leastone R is a fatty alkyl (C₁₂, C₁₄, C₁₆, C₁₈, C₂₀, or C₂₂), and the otherR is methyl, and A is a trimethylsiloxy endcap unit, provided such alkyldimethicone is a pourable liquid at room temperature. Phenyltrimethicone can be purchased from Dow Corning Corporation under thetradename 556 Fluid. Trimethylsiloxyphenyl dimethicone can be purchasedfrom Wacker-Chemie under the tradename PDM-1000. Cetyl dimethicone, alsoreferred to as a liquid silicone wax, may be purchased from Dow Corningas Fluid 2502, or from DeGussa Care & Surface Specialties under thetrade names Abil Wax 9801, or 9814.

5. Fluorinated Oils

Various types of fluorinated oils may also be suitable for use in thecompositions including but not limited to fluorinated silicones,fluorinated esters, or perfluropolyethers. Particularly suitable arefluorosilicones such as trimethylsilyl endcapped fluorosilicone oil,polytrifluoropropylmethylsiloxanes, and similar silicones such as thosedisclosed in U.S. Pat. No. 5,118,496 which is hereby incorporated byreference. Perfluoropolyethers include those disclosed in U.S. Pat. Nos.5,183,589, 4,803,067, 5,183,588, all of which are hereby incorporated byreference, which are commercially available from Montefluos under thetrademark Fomblin.

In the case where the composition is anhydrous or in the form of anemulsion, it may be desirable to include one or more oil phasestructuring agents in the cosmetic composition. The term “oil phasestructuring agent” means an ingredient or combination of ingredients,soluble or dispersible in the oil phase, which will increase theviscosity, or structure, the oil phase. The oil phase structuring agentis compatible with the Type I H⁺, K⁺-ATPase inhibitor compound orderivative thereof, particularly if the Type I H⁺, K⁺-ATPase inhibitorcompound or derivative thereof is soluble in the nonpolar oils formingthe oil phase of the composition. The term “compatible” means that theoil phase structuring agent and Type I H⁺, K⁺-ATPase inhibitor compoundor derivative thereof are capable of being formulated into a cosmeticproduct that is generally stable. The structuring agent may be presentin an amount sufficient to provide a liquid composition with increasedviscosity, a semi-solid, or in some cases a solid composition that maybe self-supporting. The structuring agent itself may be present in theliquid, semi-solid, or solid form. Suggested ranges of structuring agentare from about 0.01 to 70%, preferably from about 0.05 to 50%, morepreferably from about 0.1-35% by weight of the total composition.Suitable oil phase structuring agents include those that are siliconebased or organic based. They may be polymers or non-polymers, synthetic,natural, or a combination of both. Such oil structuring agents mayinclude the following:

A. Silicone Structuring Agents

A variety of oil phase structuring agents may be silicone based, such assilicone elastomers, silicone gums, silicone waxes, and linear siliconeshaving a degree of polymerization that provides the silicone with adegree of viscosity such that when incorporated into the cosmeticcomposition it is capable of increasing the viscosity of the oil phase.Examples of silicone structuring agents include, but are not limited to:

1. Silicone Elastomers

Silicone elastomers suitable for use in the compositions of theinvention include those that are formed by addition reaction curing, byreacting an SiH-containing diorganosiloxane and an organopolysiloxanehaving terminal olefinic unsaturation, or an alpha-omega dienehydrocarbon, in the presence of a platinum metal catalyst. Suchelastomers may also be formed by other reaction methods such ascondensation-curing organopolysiloxane compositions in the presence ofan organotin compound via a dehydrogenation reaction betweenhydroxyl-terminated diorganopolysiloxane and SiH-containingdiorganopolysiloxane or alpha omega diene; or by condensation-curingorganopolysiloxane compositions in the presence of an organotin compoundor a titanate ester using a condensation reaction between anhydroxyl-terminated diorganopolysiloxane and a hydrolysableorganosiloxane; peroxide-curing organopolysiloxane compositions whichthermally cure in the presence of an organoperoxide catalyst.

One type of elastomer that may be suitable is prepared by additionreaction-curing an organopolysiloxane having at least 2 lower alkenylgroups in each molecule or an alpha-omega diene; and anorganopolysiloxane having at least 2 silicon-bonded hydrogen atoms ineach molecule; and a platinum-type catalyst. While the lower alkenylgroups such as vinyl, can be present at any position in the molecule,terminal olefinic unsaturation on one or both molecular terminals ispreferred. The molecular structure of this component may be straightchain, branched straight chain, cyclic, or network. Theseorganopolysiloxanes are exemplified by methylvinylsiloxanes,methylvinylsiloxane-dimethylsiloxane copolymers,dimethylvinylsiloxy-terminated dimethylpolysiloxanes,dimethylvinylsiloxy-terminated dimethylsiloxane-methylphenylsiloxanecopolymers, dimethylvinylsiloxy-terminateddimethylsiloxane-diphenylsiloxane-methylvinylsiloxane copolymers,trimethylsiloxy-terminated dimethylsiloxane-methylvinylsiloxanecopolymers, trimethylsiloxy-terminateddimethylsiloxane-methylphenylsiloxane-methylvinylsiloxane copolymers,dimethylvinylsiloxy-terminated methyl(3,3,3-trifluoropropyl)polysiloxanes, and dimethylvinylsiloxy-terminateddimethylsiloxane-methyl(3,3,-trifluoropropyl)siloxane copolymers,decadiene, octadiene, heptadiene, hexadiene, pentadiene, or tetradiene,or tridiene.

Curing proceeds by the addition reaction of the silicon-bonded hydrogenatoms in the dimethyl methylhydrogen siloxane, with the siloxane oralpha-omega diene under catalysis using the catalyst mentioned herein.To form a highly crosslinked structure, the methyl hydrogen siloxanemust contain at least 2 silicon-bonded hydrogen atoms in each moleculein order to optimize function as a crosslinker.

The catalyst used in the addition reaction of silicon-bonded hydrogenatoms and alkenyl groups, and is concretely exemplified bychloroplatinic acid, possibly dissolved in an alcohol or ketone and thissolution optionally aged, chloroplatinic acid-olefin complexes,chloroplatinic acid-alkenylsiloxane complexes, chloroplatinicacid-diketone complexes, platinum black, and carrier-supported platinum.

Examples of suitable silicone elastomers for use in the compositions ofthe invention may be in the powder form, or dispersed or solubilized insolvents such as volatile or non-volatile silicones, or siliconecompatible vehicles such as paraffinic hydrocarbons or esters. Examplesof silicone elastomer powders include vinyl dimethicone/methiconesilesquioxane crosspolymers like Shin-Etsu's KSP-100, KSP-101, KSP-102,KSP-103, KSP-104, KSP-105, hybrid silicone powders that contain afluoroalkyl group like Shin-Etsu's KSP-200 which is a fluoro-siliconeelastomer, and hybrid silicone powders that contain a phenyl group suchas Shin-Etsu's KSP-300, which is a phenyl substituted siliconeelastomer; and Dow Corning's DC 9506. Examples of silicone elastomerpowders dispersed in a silicone compatible vehicle includedimethicone/vinyl dimethicone crosspolymers supplied by a variety ofsuppliers including Dow Corning Corporation under the tradenames 9040 or9041, GE Silicones under the tradename SFE 839, or Shin-Etsu Siliconesunder the tradenames KSG-15, 16, 18. KSG-15 has the CTFA namecyclopentasiloxane/dimethicone/vinyl dimethicone crosspolymer. KSG-18has the INCI name phenyl trimethicone/dimethicone/phenyl vinyldimethicone crosspolymer. Silicone elastomers may also be purchased fromGrant Industries under the Gransil trademark. Also suitable are siliconeelastomers having long chain alkyl substitutions such as lauryldimethicone/vinyl dimethicone crosspolymers supplied by Shin Etsu underthe tradenames KSG-31, KSG-32, KSG-41, KSG-42, KSG-43, and KSG-44.Cross-linked organopolysiloxane elastomers useful in the presentinvention and processes for making them are further described in U.S.Pat. No. 4,970,252; U.S. Pat. No. 5,760,116; U.S. Pat. No. 5,654,362;and Japanese Patent Application JP 61-18708; each of which is hereinincorporated by reference in its entirety. It is particularly desirableto incorporate silicone elastomers into the compositions of theinvention because they provide excellent “feel” to the composition, arevery stable in cosmetic formulations, and relatively inexpensive.

2. Silicone Gums

Also suitable for use as an oil phase structuring agent are one or moresilicone gums. The term “gum” means a silicone polymer having a degreeof polymerization sufficient to provide a silicone having a gum-liketexture. In certain cases the silicone polymer forming the gum may becrosslinked. The silicone gum typically has a viscosity ranging fromabout 500,000 to 100 million cst at 25° C., preferably from about600,000 to 20 million, more preferably from about 600,000 to 12 millioncst. All ranges mentioned herein include all subranges, e.g. 550,000;925,000; 3.5 million.

The silicone gums that are used in the compositions include, but are notlimited to, those of the general formula:

wherein R₁ to R₉ are each independently an alkyl having 1 to 30 carbonatoms, aryl, or aralkyl; and X is OH or a C₁₋₃₀ alkyl, or vinyl; andwherein x, y, or z may be zero with the proviso that no more than two ofx, y, or z are zero at any one time, and further that x, y, and z aresuch that the silicone gum has a viscosity of at least about 500,000cst, ranging up to about 100 million centistokes at 25° C. Preferred iswhere R is methyl or OH.

Such silicone gums may be purchased in pure form from a variety ofsilicone manufacturers including Wacker-Chemie or Dow Corning, and thelike. Such silicone gums include those sold by Wacker-Belsil under thetrade names CM3092, Wacker-Belsil 1000, or Wacker-Belsil DM 3096. Asilicone gum where X is OH, also referred to as dimethiconol, isavailable from Dow Corning Corporation under the trade name 1401. Thesilicone gum may also be purchased in the form of a solution ordispersion in a silicone compatible vehicle such as volatile ornonvolatile silicone. An example of such a mixture may be purchased fromBarnet Silicones under the HL-88 tradename, having the INCI namedimethicone.

3. Silicone Waxes

Another type of oily phase structuring agent includes silicone waxesthat are typically referred to as alkyl silicone waxes which aresemi-solids or solids at room temperature. The term “alkyl silicone wax”means a polydimethylsiloxane having a substituted long chain alkyl (suchas C16 to 30) that confers a semi-solid or solid property to thesiloxane. Examples of such silicone waxes include stearyl dimethicone,which may be purchased from DeGussa Care & Surface Specialties under thetradename Abil Wax 9800 or from Dow Corning under the tradename 2503.Another example is bis-stearyl dimethicone, which may be purchased fromGransil Industries under the tradename Gransil A-18, or behenyldimethicone, behenoxy dimethicone.

4. Polyamides or Silicone Polyamides

Also suitable as oil phase structuring agents are various types ofpolymeric compounds such as polyamides or silicone polyamides.

The term silicone polyamide means a polymer comprised of siliconemonomers and monomers containing amide groups as further describedherein. The silicone polyamide preferably comprises moieties of thegeneral formula:

X is a linear or branched alkylene having from about 1-30 carbon atoms;R₁, R₂, R₃, and R₄ are each independently C₁₋₃₀ straight or branchedchain alkyl which may be substituted with one or more hydroxyl orhalogen groups; phenyl which may be substituted with one or more C₁₋₃₀alkyl groups, halogen, hydroxyl, or alkoxy groups; or a siloxane chainhaving the general formula:

and Y is:

-   -   (a) a linear or branched alkylene having from about 1-40 carbon        atoms which may be substituted with:        -   (i) one or more amide groups having the general formula            R₁CONR₁, or        -   (ii) C₅₋₆ cyclic ring, or        -   (iii) phenylene which may be substituted with one or more            C₁₋₁₀ alkyl groups, or        -   (iv) hydroxy, or        -   (v) C₃₋₈ cycloalkane, or        -   (vi) C₁₋₂₀ alkyl which may be substituted with one or more            hydroxy groups, or        -   (vii) C₁₋₁₀ alkyl amines; or    -   (b) TR₅R₆R₇        wherein R₅, R₆, and R₇, are each independently a C₁₋₁₀ linear or        branched alkylenes, and T is CR₈ wherein R₅ is hydrogen, a        trivalent atom N, P, or Al, or a C₁₋₃₀ straight or branched        chain alkyl which may be substituted with one or more hydroxyl        or halogen groups; phenyl which may be substituted with one or        more C₁₋₃₀ alkyl groups, halogen, hydroxyl, or alkoxy groups; or        a siloxane chain having the general formula:

Preferred is where R₁, R₂, R₃, and R₄ are C₁₋₁₀, preferably methyl; andX and Y are a linear or branched alkylene. Preferred are siliconepolyamides having the general formula:

wherein a and b are each independently sufficient to provide a siliconepolyamide polymer having a melting point ranging from about 60 to 120°C., and a molecular weight ranging from about 40,000 to 500,000 Daltons.One type of silicone polyamide that may be used in the compositions ofthe invention may be purchased from Dow Corning Corporation under thetradename Dow Corning 2-8178 gellant which has the CTFA namenylon-611/dimethicone copolymer which is sold in a compositioncontaining PPG-3 myristyl ether.

Also suitable are polyamides such as those purchased from ArizonaChemical under the tradenames Uniclear and Sylvaclear. Such polyamidesmay be ester terminated or amide terminated. Examples of esterterminated polyamides include, but are not limited to those having thegeneral formula:

wherein n denotes a number of amide units such that the number of estergroups ranges from about 10% to 50% of the total number of ester andamide groups; each R₁ is independently an alkyl or alkenyl groupcontaining at least 4 carbon atoms; each R₂ is independently a C₄₋₄₂hydrocarbon group, with the proviso that at least 50% of the R₂ groupsare a C₃₀₋₄₂ hydrocarbon; each R₃ is independently an organic groupcontaining at least 2 carbon atoms, hydrogen atoms and optionally one ormore oxygen or nitrogen atoms; and each R₄ is independently a hydrogenatom, a C₁₋₁₀ alkyl group or a direct bond to R₃ or to another R₄, suchthat the nitrogen atom to which R₃ and R₄ are both attached forms partof a heterocyclic structure defined by R₄—N—R₃, with at least 50% of thegroups R4 representing a hydrogen atom.

General examples of ester and amide terminated polyamides that may beused as oil phase gelling agents include those sold by Arizona Chemicalunder the tradenames Sylvaclear A200V or A2614V, both having the CTFAname ethylenediamine/hydrogenated dimer dilinoleatecopolymer/bis-di-C₁₄₋₁₈ alkyl amide; Sylvaclear AF1900V; Sylvaclear C75Vhaving the CTFA name bis-stearyl ethylenediamine/neopentylglycol/stearyl hydrogenated dimer dilinoleate copolymer; SylvaclearPA1200V having the CTFA name Polyamide-3; Sylvaclear PE400V; SylvaclearWF1500V; or Uniclear, such as Uniclear 100VG having the INCI nameethylenediamine/stearyl dimer dilinoleate copolymer; orethylenediamine/stearyl dimer ditallate copolymer. Other examples ofsuitable polyamides include those sold by Henkel under the Versamidtrademark (such as Versamid 930, 744, 1655), or by Olin MathiesonChemical Corp. under the brand name Onamid S or Onamid C.

5. Natural or Synthetic Organic Waxes

Also suitable as the oil phase structuring agent may be one or morenatural or synthetic waxes such as animal, vegetable, or mineral waxes.Preferably such waxes will have a higher melting point such as fromabout 50 to 150° C., more preferably from about 65 to 100° C. Examplesof such waxes include waxes made by Fischer-Tropsch synthesis, such aspolyethylene or synthetic wax; or various vegetable waxes such asbayberry, candelilla, ozokerite, acacia, beeswax, ceresin, cetyl esters,flower wax, citrus wax, carnauba wax, jojoba wax, japan wax,polyethylene, microcrystalline, rice bran, lanolin wax, mink, montan,bayberry, ouricury, ozokerite, palm kernel wax, paraffin, avocado wax,apple wax, shellac wax, clary wax, spent grain wax, grape wax, andpolyalkylene glycol derivatives thereof such as PEG6-20 beeswax, orPEG-12 carnauba wax; or fatty acids or fatty alcohols, including estersthereof, such as hydroxystearic acids (for example 12-hydroxy stearicacid), tristearin, tribehenin, and so on.

6. Montmorillonite Minerals

One type of structuring agent that may be used in the compositioncomprises natural or synthetic montmorillonite minerals such ashectorite, bentonite, and quaternized derivatives thereof, which areobtained by reacting the minerals with a quaternary ammonium compound,such as stearalkonium bentonite, hectorites, quaternized hectorites suchas Quaternium-18 hectorite, attapulgite, carbonates such as propylenecarbonate, bentones, and the like.

7. Silicas and Silicates

Another type of structuring agent that may be used in the compositionsare silicas, silicates, silica silylate, and alkali metal or alkalineearth metal derivatives thereof. These silicas and silicates aregenerally found in the particulate form and include silica, silicasilylate, magnesium aluminum silicate, and the like.

The composition may contain one or more surfactants, especially if inthe emulsion form. However, such surfactants may be used if thecompositions are anhydrous also, and will assist in dispersingingredients that have polarity, for example pigments. Such surfactantsmay be silicone or organic based. The surfactants will aid in theformation of stable emulsions of either the water-in-oil or oil-in-waterform. If present, the surfactant may range from about 0.001 to 30%,preferably from about 0.005 to 25%, more preferably from about 0.1 to20% by weight of the total composition.

A. Silicone Surfactants

Suitable silicone surfactants include polyorganosiloxane polymers thathave amphiphilic properties, for example contain hydrophilic radicalsand lipophilic radicals. These silicone surfactants may be liquids orsolids at room temperature.

1. Dimethicone Copolyols or Alkyl Dimethicone Copolyols

One type of silicone surfactant that may be used is generally referredto as dimethicone copolyol or alkyl dimethicone copolyol. Thissurfactant is either a water-in-oil or oil-in-water surfactant having anHydrophile/Lipophile Balance (HLB) ranging from about 2 to 18.Preferably the silicone surfactant is a nonionic surfactant having anHLB ranging from about 2 to 12, preferably about 2 to 10, mostpreferably about 4 to 6. The term “hydrophilic radical” means a radicalthat, when substituted onto the organosiloxane polymer backbone, confershydrophilic properties to the substituted portion of the polymer.Examples of radicals that will confer hydrophilicity arehydroxy-polyethyleneoxy, hydroxyl, carboxylates, and mixtures thereof.The term “lipophilic radical” means an organic radical that, whensubstituted onto the organosiloxane polymer backbone, confers lipophilicproperties to the substituted portion of the polymer. Examples oforganic radicals that will confer lipophilicity are C₁₋₄₀ straight orbranched chain alkyl, fluoro, aryl, aryloxy, C₁₋₄₀ hydrocarbyl acyl,hydroxy-polypropyleneoxy, or mixtures thereof.

One type of suitable silicone surfactant has the general formula:

wherein p is 0-40 (the range including all numbers between and subrangessuch as 2, 3, 4, 13, 14, 15, 16, 17, 18, etc.), and PE is(—C₂H₄O)_(a)—(—C₃H₆O)_(b)—H wherein a is 0 to 25, b is 0-25 with theproviso that both a and b cannot be 0 simultaneously, x and y are eachindependently ranging from 0 to 1 million with the proviso that theyboth cannot be 0 simultaneously. In one preferred embodiment, x, y, z,a, and b are such that the molecular weight of the polymer ranges fromabout 5,000 to about 500,000, more preferably from about 10,000 to100,000, and is most preferably approximately about 50,000 and thepolymer is generically referred to as dimethicone copolyol.One type of silicone surfactant is wherein p is such that the long chainalkyl is cetyl or lauryl, and the surfactant is called, generically,cetyl dimethicone copolyol or lauryl dimethicone copolyol respectively.

In some cases the number of repeating ethylene oxide or propylene oxideunits in the polymer are also specified, such as a dimethicone copolyolthat is also referred to as PEG-15/PPG-10 dimethicone, which refers to adimethicone having substituents containing 15 ethylene glycol units and10 propylene glycol units on the siloxane backbone. It is also possiblefor one or more of the methyl groups in the above general structure tobe substituted with a longer chain alkyl (e.g. ethyl, propyl, butyl,etc.) or an ether such as methyl ether, ethyl ether, propyl ether, butylether, and the like.

Examples of silicone surfactants are those sold by Dow Corning under thetradename Dow Corning 3225C Formulation Aid having the CTFA namecyclotetrasiloxane (and) cyclopentasiloxane (and) PEG/PPG-18dimethicone; or 5225C Formulation Aid, having the CTFA namecyclopentasiloxane (and) PEG/PPG-18/18 dimethicone; or Dow Corning 190Surfactant having the CTFA name PEG/PPG-18/18 dimethicone; or DowCorning 193 Fluid, Dow Corning 5200 having the CTFA name laurylPEG/PPG-18/18 methicone; or Abil EM 90 having the CTFA name cetylPEG/PPG-14/14 dimethicone sold by Goldschmidt; or Abil EM 97 having theCTFA name bis-cetyl PEG/PPG-14/14 dimethicone sold by Goldschmidt; orAbil WE 09 having the CTFA name cetyl PEG/PPG-10/1 dimethicone in amixture also containing polyglyceryl-4 isostearate and hexyl laurate; orKF-6011 sold by Shin-Etsu Silicones having the CTFA name PEG-11 methylether dimethicone; KF-6012 sold by Shin-Etsu Silicones having the CTFAname PEG/PPG-20/22 butyl ether dimethicone; or KF-6013 sold by Shin-EtsuSilicones having the CTFA name PEG-9 dimethicone; or KF-6015 sold byShin-Etsu Silicones having the CTFA name PEG-3 dimethicone; or KF-6016sold by Shin-Etsu Silicones having the CTFA name PEG-9 methyl etherdimethicone; or KF-6017 sold by Shin-Etsu Silicones having the CTFA namePEG-10 dimethicone; or KF-6038 sold by Shin-Etsu Silicones having theCTFA name lauryl PEG-9 polydimethylsiloxyethyl dimethicone.

2. Crosslinked Silicone Surfactants

Also suitable are various types of crosslinked silicone surfactants thatare often referred to as emulsifying elastomers. They are typicallyprepared as set forth above with respect to the section “siliconeelastomers” except that the silicone elastomers will contain at leastone hydrophilic moiety such as polyoxyalkylenated groups. Typicallythese polyoxyalkylenated silicone elastomers are crosslinkedorganopolysiloxanes that may be obtained by a crosslinking additionreaction of diorganopolysiloxane comprising at least one hydrogen bondedto silicon and of a polyoxyalkylene comprising at least twoethylenically unsaturated groups. In at least one embodiment, thepolyoxyalkylenated crosslinked organo-polysiloxanes are obtained by acrosslinking addition reaction of a diorganopolysiloxane comprising atleast two hydrogens each bonded to a silicon, and a polyoxyalkylenecomprising at least two ethylenically unsaturated groups, optionally inthe presence of a platinum catalyst, as described, for example, in U.S.Pat. No. 5,236,986, U.S. Pat. No. 5,412,004, U.S. Pat. No. 5,837,793 andU.S. Pat. No. 5,811,487, the contents of which are hereby incorporatedby reference in their entireties.

Polyoxyalkylenated silicone elastomers that may be used in at least oneembodiment of the invention include those sold by Shin-Etsu Siliconesunder the names KSG-21, KSG-20, KSG-30, KSG-31, KSG-32, KSG-33; KSG-210which is dimethicone/PEG-10/15 crosspolymer dispersed in dimethicone;KSG-310 which is PEG-15 lauryl dimethicone crosspolymer; KSG-320 whichis PEG-15 lauryl dimethicone crosspolymer dispersed in isododecane;KSG-330 (the former dispersed in triethylhexanoin), KSG-340 which is amixture of PEG-10 lauryl dimethicone crosspolymer and PEG-15 lauryldimethicone crosspolymer.

Also suitable are polyglycerolated silicone elastomers like thosedisclosed in PCT/WO 2004/024798, which is hereby incorporated byreference in its entirety. Such elastomers include Shin-Etsu's KSGseries, such as KSG-710 which is dimethicone/polyglycerin-3 crosspolymerdispersed in dimethicone; or lauryl dimethicone/polyglycerin-3crosspolymer dispersed in a variety of solvent such as isododecane,dimethicone, triethylhexanoin, sold under the Shin-Etsu tradenamesKSG-810, KSG-820, KSG-830, or KSG-840. Also suitable are silicones soldby Dow Corning under the tradenames 9010 and DC9011.

One preferred crosslinked silicone elastomer emulsifier isdimethicone/PEG-10/15 crosspolymer, which provides excellent aestheticsdue to its elastomeric backbone, but also surfactancy properties.

B. Organic Nonionic Surfactants

The composition may comprise one or more nonionic organic surfactants.Suitable nonionic surfactants include alkoxylated alcohols, or ethers,formed by the reaction of an alcohol with an alkylene oxide, usuallyethylene or propylene oxide. Preferably the alcohol is either a fattyalcohol having 6 to 30 carbon atoms. Examples of such ingredientsinclude Steareth 2-100, which is formed by the reaction of stearylalcohol and ethylene oxide and the number of ethylene oxide units rangesfrom 2 to 100; Beheneth 5-30 which is formed by the reaction of behenylalcohol and ethylene oxide where the number of repeating ethylene oxideunits is 5 to 30; Ceteareth 2-100, formed by the reaction of a mixtureof cetyl and stearyl alcohol with ethylene oxide, where the number ofrepeating ethylene oxide units in the molecule is 2 to 100; Ceteth 1-45which is formed by the reaction of cetyl alcohol and ethylene oxide, andthe number of repeating ethylene oxide units is 1 to 45, and so on.

Other alkoxylated alcohols are formed by the reaction of fatty acids andmono-, di- or polyhydric alcohols with an alkylene oxide. For example,the reaction products of C₆₋₃₀ fatty carboxylic acids and polyhydricalcohols which are monosaccharides such as glucose, galactose, methylglucose, and the like, with an alkoxylated alcohol. Examples includepolymeric alkylene, glycols reacted with glyceryl fatty acid esters suchas PEG glyceryl oleates, PEG glyceryl stearate; or PEGpolyhydroxyalkanotes such as PEG dipolyhydroxystearate wherein thenumber of repeating ethylene glycol units ranges from 3 to 1000.

Also suitable as nonionic surfactants are those formed by the reactionof a carboxylic acid with an alkylene oxide or with a polymeric ether.The resulting products have the general formula:

where RCO is the carboxylic ester radical, X is hydrogen or lower alkyl,and n is the number of polymerized alkoxy groups. In the case of thediesters, the two RCO-groups do not need to be identical. Preferably, Ris a C6-30 straight or branched chain, saturated or unsaturated alkyl,and n is from 1-100.

Monomeric, homopolymeric, or block copolymeric ethers are also suitableas nonionic surfactants. Typically, such ethers are formed by thepolymerization of monomeric alkylene oxides, generally ethylene orpropylene oxide. Such polymeric ethers have the following generalformula:

wherein R is H or lower alkyl and n is the number of repeating monomerunits, and ranges from 1 to 500.

Other suitable nonionic surfactants include alkoxylated sorbitan andalkoxylated sorbitan derivatives. For example, alkoxylation, inparticular ethoxylation of sorbitan provides polyalkoxylated sorbitanderivatives. Esterification of polyalkoxylated sorbitan providessorbitan esters such as the polysorbates. For example, thepolyalkyoxylated sorbitan can be esterified with C6-30, preferablyC12-22 fatty acids. Examples of such ingredients include Polysorbates20-85, sorbitan oleate, sorbitan sesquioleate, sorbitan palmitate,sorbitan sesquiisostearate, sorbitan stearate, and so on.

Certain types of amphoteric, zwitterionic, or cationic surfactants mayalso be used in the compositions. Descriptions of such surfactants areset forth in U.S. Pat. No. 5,843,193, which is hereby incorporated byreference in its entirety.

It may be desirable to include one or more penetration enhancers in thecomposition. Penetration enhancers are ingredients that enhance thepenetration of the Type I H⁺, K⁺-ATPase inhibitor compound or derivativethereof into the keratinous surface to which the composition is applied.If present, suitable penetration enhancers may range from about 0.001 to30%, preferably from about 0.005 to 25%, more preferably from about 0.01to 20%. Suitable penetration enhancers include, but are not limited tolipophilic materials such as saturated or unsaturated C₆₋₄₀ straight orbranched chain fatty acids, or saturated or unsaturated C₆₋₄₀ straightor branched chain fatty alcohols. Examples include oleic acid, linoleicacid, stearic acid, oleyl alcohol, linoleyl alcohol, and the like.

It may also be desirable to include one or more humectants in thecomposition. If present, such humectants may range from about 0.001 to25%, preferably from about 0.005 to 20%, more preferably from about 0.1to 15% by weight of the total composition. Examples of suitablehumectants include glycols, sugars, and the like. Suitable glycols arein monomeric or polymeric form and include polyethylene andpolypropylene glycols such as PEG 4-200, which are polyethylene glycolshaving from 4 to 200 repeating ethylene oxide units; as well as C₁₋₆alkylene glycols such as propylene glycol, butylene glycol, pentyleneglycol, and the like. Suitable sugars, some of which are also polyhydricalcohols, are also suitable humectants. Examples of such sugars includeglucose, fructose, honey, hydrogenated honey, inositol, maltose,mannitol, maltitol, sorbitol, sucrose, xylitol, xylose, and so on. Alsosuitable is urea. Preferably, the humectants used in the composition ofthe invention are C₁₋₆, preferably C₂₄ alkylene glycols, mostparticularly butylene glycol.

It may be desirable to include one or more botanical extracts in thecompositions. If so, suggested ranges are from about 0.0001 to 10%,preferably about 0.0005 to 8%, more preferably about 0.001 to 5% byweight of the total composition. Suitable botanical extracts includeextracts from plants (herbs, roots, flowers, fruits, seeds) such asflowers, fruits, vegetables, and so on, including yeast ferment extract,Padina pavonica extract, Thermus thermophilis ferment extract, Camelinasaliva seed oil, Boswellia serrata extract, olive extract, Aribodopsisthaliana extract, Acacia dealbata extract, Acer saccharimum (sugarmaple), acidopholus, acorus, aesculus, agaricus, agave, agrimonia,algae, aloe, citrus, brassica, cinnamon, orange, apple, blueberry,cranberry, peach, pear, lemon, lime, pea, seaweed, caffeine, green tea,chamomile, willowbark, mulberry, poppy, and those set forth on pages1646 through 1660 of the CTFA Cosmetic Ingredient Handbook, EighthEdition, Volume 2. Further specific examples include, but are notlimited to, Glycyrrhiza glabra, Salix nigra, Macrocycstis pyrifera,Pynrus malus, Saxifraga sarmentosa, Vitis vinifera, Morus nigra,Scutellaria baicalensis, Anthemis nobilis, Salvia sclarea, Rosmarinusofficianalis, Citrus medica Limonum, Panax, Ginseng, Siegesbeckiaorientalis, Fructus mume, Ascophyllum nodosum, Bifida Ferment lysate,Glycine soja extract, Beta vulgaris, Haberlea rhodopensis, Polygonumcuspidatum, Citrus Aurantium dulcis, Vitis vinifera, Selaginellatamariscina, Humulus lupulus, Citrus reticulata Peel, Punica granatum,Asparagopsis, Curcuma longa, Menyanthes trifoliata, Helianthus anmuus,Hordeum vulgare, Cucumis sativus, Evernia prunastri, Evernia furfuracea,and mixtures thereof.

It may be desirable to include one or more tyrosinase inhibiting agentsin the compositions of the invention. Such tyrosinase inhibitors mayinclude kojic acid, arbutin and hydroquinone.

It may be desirable to include one or more additional skin-lighteningcompounds in the compositions of the present invention. Suitableskin-lightening compounds include ascorbic acid and its derivatives,e.g., magnesium ascorbyl phosphate, ascorbyl glucosamine, ascorbylpalmitate. Other skin-lightening agents include adapalene, aloe extract,ammonium lactate, anethole derivatives, apple extract, azelaic acid,bamboo extract, bearberry extract, bletilla tuber, Bupleurum falcatumextract, burnet extract, butyl hydroxy anisole, butyl hydroxy toluene,deoxyarbutin, 1,3 diphenyl propane derivatives, 2,5 dihydroxybenzoicacid and its derivatives, 2-(4-acetoxyphenyl)-1,3 dithane,2-(4-hydroxyphenyl)-1,3 dithane, ellagic acid, escinol, estragolederivatives, FADE OUT (available from Pentapharm), Fangfeng, fennelextract, ganoderma extract, gaoben, GATULINE WHITENING (available fromGattlefosse), genistic acid and its derivatives, glabridin and itsderivatives, gluco pyranosyl-1-ascorbate, gluconic acid, glycolic acid,green tea extract, placenta extract, 4-Hydroxy-5-methyl-3[2H]-furanone,4 hydroxyanisole and its derivatives, 4-hydroxy benzoic acidderivatives, hydroxycaprylic acid, inositol ascorbate, lactic acid,lemon extract, linoleic acid, MELA WHITE (available from Pentapharm),Morus alba extract, mulberry root extract, niacinamide, 5-octanoylsalicylic acid, parsley extract, phellinus linteus extract, pyrogallolderivatives, retinoic acid, retinol, retinyl esters (acetate,propionate, palmitate, linoleate), 2,4 resorcinol derivatives, 3,5resorcinol derivatives, rose fruit extract, salicylic acid, 3,4,5trihydroxybenzyl derivatives, tranexamic acid, vitamin D3 and itsanalogs, and mixtures thereof.

It may also be desirable to include one or more sunscreens in thecompositions of the invention. Such sunscreens include chemical UVA orUVB sunscreens or physical sunscreens in the particulate form. Inclusionof sunscreens in the compositions containing the Type I H⁺, K⁺-ATPaseinhibitor compound or derivative thereof will provide additionalprotection to skin during daylight hours and promote the effectivenessof the Type I H⁺, K⁺-ATPase inhibitor compound or derivative thereof onthe skin. Such sunscreen compounds may include the following:

A. UVA Chemical Sunscreens

If desired, the composition may comprise one or more UVA sunscreens. Theterm “UVA sunscreen” means a chemical compound that blocks UV radiationin the wavelength range of about 320 to 400 nm. Preferred UVA sunscreensare dibenzoylmethane compounds having the general formula:

wherein R₁ is H, OR and NRR wherein each R is independently H, C₁₋₂₀straight or branched chain alkyl; R₂ is H or OH; and R₃ is H, C₁₋₂₀straight or branched chain alkyl.

Preferred is where R₁ is OR where R is a C₁₋₂₀ straight or branchedalkyl, preferably methyl; R₂ is H; and R₃ is a C₁₋₂₀ straight orbranched chain alkyl, more preferably, butyl.

Examples of suitable UVA sunscreen compounds of this general formulainclude 4-methyldibenzoylmethane, 2-methyldibenzoylmethane,4-isopropyldibenzoylmethane, 4-tert-butyldibenzoylmethane,2,4-dimethyldibenzoylmethane, 2,5-dimethyldibenzoylmethane,4,4′diisopropylbenzoylmethane, 4-tert-butyl-4′-methoxydibenzoylmethane,4,4′-diisopropylbenzoylmethane,2-methyl-5-isopropyl-4′-methoxydibenzoymethane,2-methyl-5-tert-butyl-4′-methoxydibenzoylmethane, and so on.Particularly preferred is 4-tert-butyl-4′-methoxydibenzoylmethane, alsoreferred to as Avobenzone. Avobenzone is commercial available fromGivaudan-Roure under the trademark Parsol 1789, and Merck & Co. underthe tradename Eusolex 9020.

Other types of UVA sunscreens include dicamphor sulfonic acidderivatives, such as ecamsule, a sunscreen sold under the trade nameMexoryl™, which is terephthalylidene dicamphor sulfonic acid, having theformula:

The composition may contain from about 0.001-20%, preferably 0.005-5%,more preferably about 0.005-3% by weight of the composition of UVAsunscreen. In the preferred embodiment of the invention the UVAsunscreen is Avobenzone, and it is present at not greater than about 3%by weight of the total composition.

B. UVB Chemical Sunscreens

The term “UVB sunscreen” means a compound that blocks UV radiation inthe wavelength range of from about 290 to 320 nm. A variety of UVBchemical sunscreens exist including alpha-cyano-beta,beta-diphenylacrylic acid esters as set forth in U.S. Pat. No. 3,215,724, which ishereby incorporated by reference in its entirety. One particular exampleof an alpha-cyano-beta,beta-diphenyl acrylic acid ester is Octocrylene,which is 2-ethylhexyl 2-cyano-3,3-diphenylacrylate. In certain cases thecomposition may contain no more than about 110% by weight of the totalcomposition of octocrylene. Suitable amounts range from about 0.001-10%by weight. Octocrylene may be purchased from BASF under the tradenameUvinul N-539.

Other suitable sunscreens include benzylidene camphor derivatives as setforth in U.S. Pat. No. 3,781,417, which is hereby incorporated byreference in its entirety. Such benzylidene camphor derivatives have thegeneral formula:

wherein R is p-tolyl or styryl, preferably styryl. Particularlypreferred is 4-methylbenzylidene camphor, which is a lipid soluble UVBsunscreen compound sold under the tradename Eusolex 6300 by Merck.

Also suitable are cinnamate derivatives having the general formula:

wherein R and R₁ are each independently a C₁₋₂₀ straight or branchedchain alkyl. Preferred is where R is methyl and R₁ is a branched chainC₁₋₁₀, preferably C₈ alkyl. The preferred compound is ethylhexylmethoxycinnamate, also referred to as Octoxinate or octylmethoxycinnamate. The compound may be purchased from GivaudanCorporation under the tradename Parsol MCX, or BASF under the tradenameUvinul MC 80. Also suitable are mono-, di-, and triethanolaminederivatives of such methoxy cinnamates including diethanolaminemethoxycinnamate. Cinoxate, the aromatic ether derivative of the abovecompound is also acceptable. If present, the Cinoxate should be found atno more than about 3% by weight of the total composition.

Also suitable as UVB screening agents are various benzophenonederivatives having the general formula:

wherein R through R₉ are each independently H, OH, NaO₃S, SO₃H, SO₃Na,Cl, R″, OR″ where R″ is C₁₋₂₀ straight or branched chain alkyl Examplesof such compounds include Benzophenone 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, and 12. Particularly preferred is where the benzophenone derivativeis Benzophenone 3 (also referred to as Oxybenzone), Benzophenone 4 (alsoreferred to as Sulisobenzone), Benzophenone 5 (Sulisobenzone Sodium),and the like. Most preferred is Benzophenone 3.

Also suitable are certain menthyl salicylate derivatives having thegeneral formula:

wherein R₁, R₂, R₃, and R₄ are each independently H, OH, NH₂, or C₁₋₂₀straight or branched chain alkyl. Particularly preferred is where R₁,R₂, and R₃ are methyl and R₄ is hydroxyl or NH₂, the compound having thename homomenthyl salicylate (also known as Homosalate) or menthylanthranilate. Homosalate is available commercially from Merck under thetradename Eusolex HMS and menthyl anthranilate is commercially availablefrom Haarmann & Reimer under the tradename Heliopan. If present, theHomosalate should be found at no more than about 15% by weight of thetotal composition.

Various amino benzoic acid derivatives are suitable UVB absorbersincluding those having the general formula:

wherein R₁, R₂, and R₃ are each independently H, C₁₋₂₀ straight orbranched chain alkyl which may be substituted with one or more hydroxygroups. Particularly preferred is wherein R₁ is H or C₁₋₈ straight orbranched alkyl, and R₂ and R₃ are H, or C₁₋₈ straight or branched chainalkyl. Particularly preferred are PABA, ethyl hexyl dimethyl PABA(Padimate O), ethyldihydroxypropyl PABA, and the like. If presentPadimate O should be found at no more than about 8% by weight of thetotal composition.

Salicylate derivatives are also acceptable UVB absorbers. Such compoundshave the general formula:

wherein R is a straight or branched chain alkyl, including derivativesof the above compound formed from mono-, di-, or triethanolamines.Particular preferred are octyl salicylate, TEA-salicylate,DEA-salicylate, and mixtures thereof.

Generally, the amount of the UVB chemical sunscreen present may rangefrom about 0.001-45%, preferably 0.005-40%, more preferably about0.01-35% by weight of the total composition.

If desired, the compositions of the invention may be formulated to havea certain SPF (sun protective factor) values ranging from about 1-50,preferably about 2-45, most preferably about 5-30. Calculation of SPFvalues is well known in the art.

The compositions of the invention may contain particulate materials inthe form of pigments, inert particulates, or mixtures thereof. Ifpresent, suggested ranges are from about 0.01-75%, preferably about0.5-70%, more preferably about 0.1-65% by weight of the totalcomposition. In the case where the composition may comprise mixtures ofpigments and powders, suitable ranges include about 0.01-75% pigment and0.1-75% powder, such weights by weight of the total composition.Suitable particulate materials may include the following:

A. Powders

The particulate matter may be colored or non-colored (for example white)non-pigmented powders. Suitable non-pigmented powders include bismuthoxychloride, titanated mica, fumed silica, spherical silica,polymethylmethacrylate, micronized teflon, boron nitride, acrylatecopolymers, aluminum silicate, aluminum starch octenylsuccinate,bentonite, calcium silicate, cellulose, chalk, corn starch, diatomaceousearth, fuller's earth, glyceryl starch, hectorite, hydrated silica,kaolin, magnesium aluminum silicate, magnesium trisilicate,maltodextrin, montmorillonite, microcrystalline cellulose, rice starch,silica, talc, mica, titanium dioxide, zinc laurate, zinc myristate, zincrosinate, alumina, attapulgite, calcium carbonate, calcium silicate,dextran, kaolin, nylon, silica silylate, silk powder, sericite, soyflour, tin oxide, titanium hydroxide, trimagnesium phosphate, walnutshell powder, or mixtures thereof. The above mentioned powders may besurface treated with lecithin, amino acids, mineral oil, silicone, orvarious other agents either alone or in combination, which coat thepowder surface and render the particles more lipophilic in nature.

B. Pigments

The particulate materials may comprise various organic and/or inorganicpigments. The organic pigments are generally various aromatic typesincluding azo, indigoid, triphenylmethane, anthroquinone, and xanthinedyes which are designated as D&C and FD&C blues, browns, greens,oranges, reds, yellows, etc. Organic pigments generally consist ofinsoluble metallic salts of certified color additives, referred to asthe Lakes. Inorganic pigments include iron oxides, ultramarines,chromium, chromium hydroxide colors, and mixtures thereof. Iron oxidesof red, blue, yellow, brown, black, and mixtures thereof are suitable.

The composition may contain 0.001-8%, preferably 0.01-6%, morepreferably 0.05-5% by weight of the total composition of preservatives.A variety of preservatives are suitable, including such as benzoic acid,benzyl alcohol, benzylhemiformal, benzylparaben,5-bromo-5-nitro-1,3-dioxane, 2-bromo-2-nitropropane-1,3-diol, butylparaben, phenoxyethanol, methyl paraben, propyl paraben, diazolidinylurea, calcium benzoate, calcium propionate, caprylyl glycol, biguanidederivatives, phenoxyethanol, captan, chlorhexidine diacetate,chlorhexidine digluconate, chlorhexidine dihydrochloride,chloroacetamide, chlorobutanol, p-chloro-m-cresol, chlorophene,chlorothymol, chloroxylenol, m-cresol, o-cresol, DEDM Hydantoin, DEDMHydantoin dilaurate, dehydroacetic acid, diazolidinyl urea,dibromopropamidine diisethionate, DMDM Hydantoin, and the like. In onepreferred embodiment the composition is free of parabens.

The compositions of the invention may contain vitamins and/or coenzymes,as well as antioxidants. If so, 0.001-10%, preferably 0.01-8%, morepreferably 0.05-5% by weight of the total composition is suggested.Suitable vitamins include ascorbic acid and derivatives thereof such asascorbyl palmitate, tetrahexydecyl ascorbate, and so on; the B vitaminssuch as thiamine, riboflavin, pyridoxin, niacin, niacinamide, nicotinicacid, nicotinic acid dinucleotide, and so on, as well as coenzymes suchas thiamine pyrophoshate, flavin adenine dinucleotide, folic acid,pyridoxal phosphate, tetrahydrofolic acid, and so on. Also Vitamin A andderivatives thereof are suitable. Examples are retinyl palmitate,retinol, retinoic acid, as well as Vitamin A in the form of betacarotene. Also suitable is Vitamin E and derivatives thereof such asVitamin E acetate, nicotinate, or other esters thereof. In addition,Vitamins D and K are suitable.

Suitable antioxidants are ingredients which assist in preventing orretarding spoilage. Examples of antioxidants suitable for use in thecompositions of the invention are potassium sulfite, sodium bisulfite,sodium erythrobate, sodium metabisulfite, sodium sulfite, propylgallate, cysteine hydrochloride, butylated hydroxytoluene, butylatedhydroxyanisole, and so on.

It may be desirable to include one or more film forming ingredients inthe cosmetic compositions of the invention. Suitable film formers areingredients that contribute to formation of a film on the keratinoussurface. In some cases the film formers may provide films that providelong wearing or transfer resistant properties such that the cosmeticapplied to the keratinous surface will remain for periods of timeranging from 3 to 16 hours. If present, such film formers may range fromabout 0.01 to 50%, preferably from about 0.1 to 40%, more preferablyfrom about 0.5 to 35% by weight of the total composition. The filmformers are most often found in the polymeric form and may be natural orsynthetic polymers. If synthetic, silicone polymers, organic polymers orcopolymers of silicones and organic groups may be acceptable. Suitablefilm formers include, but are not limited to:

A. Silicone Resins

One particularly suitable type of silicone film former is a siliconeresin. Silicone resins are generally highly crosslinked structurescomprising combinations of M, D, T, and Q units. The term “M” means amonofunctional siloxy unit having the general formula:

[Si—(CH₃)₃—O]_(0.5)

In cases where the M unit is other than methyl (such as ethyl, propyl,ethoxy, etc.) the M unit may have a prime after it, e.g. M′.

The term “D” means a difunctional siloxy unit having the generalformula:

[Si—(CH₃)₂—O]_(1.0)

The difunctional unit may be substituted with alkyl groups other thanmethyl, such as ethyl, propyl, alkylene glycol, and the like, in whichcase the D unit may be referred to as D′, with the prime indicating asubstitution.

The term “T” means a trifunctional siloxy unit having the generalformula:

[Si—(CH₃)—O]_(1.5)

The trifunctional unit may be substituted with substituents other thanmethyl, in which case it may be referred to as T′.

The term “Q” refers to a quadrifunctional siloxy unit having the generalformula:

[Si—O-]_(2.0)

The silicone resins that may be used as film formers in the compositionsof the invention preferably comprise highly crosslinked combinations ofM, T, and Q units. Examples of such resins includetrimethylsiloxysilicate which can be purchased from Dow CorningCorporation as 749 Fluid, or from GE Silicones under the SR-1000tradename. Also suitable is a silicone resin that contains a largepercentage of T groups, such as MK resin sold by Wacker-Chemie, havingthe CTFA name polymethylsilsesquioxane.

B. Copolymers of Silicone and Organic Monomers

Also suitable for use as the film formers are copolymers of silicone andorganic monomers such as acrylates, methacrylates, and the like.Examples of such suitable film forming polymers include those commonlyreferred to as silicone acrylate or vinyl silicone copolymers, such asthose sold by 3M under the brand name “Silicone Plus” polymers such asSA-70, having the CTFA name Polysilicone-7 and is a copolymer ofisobutylmethacrylate and n-butyl endblocked polydimethylsiloxane propylmethacrylate; or VS-70 having the CTFA name Polysilicone-6, which is acopolymer of dimethylsiloxane and methyl-3 mercaptopropyl siloxanereacted with isobutyl methacrylate; or VS-80, having the CTFA namePolysilicone-8, which has the general structure:

where R represents the acrylates copolymer radical.

C. Organic Polymers

Also suitable as film formers include various types of organic polymerssuch as polymers formed from acrylic acid, methacrylic acid, or theirsimple C₁₋₁₀ carboxylic acid esters, such as methyl methacrylate, methylacrylate, and the like.

Also suitable are various types of natural polymers such as shellac,natural resins, chitin, and the like.

It may also be desirable to incorporate one or more DNA repair enzymesinto the composition of the invention. Suggested ranges are from about0.00001 to about 35%, preferably from about 0.00005 to about 30%, morepreferably from about 0.0001 to about 25% of one or more DNA repairenzymes.

DNA repair enzymes as disclosed in U.S. Pat. Nos. 5,077,211; 5,190,762;5,272,079; and 5,296,231, all of which are hereby incorporated byreference in their entirety, are suitable for use in the compositionsand method of the invention. One example of such a DNA repair enzyme maybe purchased from AGI Dermatics under the trade name Roxisomes®, and hasthe INCI name Arabidopsis Thaliana extract. It may be present alone orin admixture with lecithin and water. This DNA repair enzyme is known tobe effective in repairing 8-oxo-diGuanine base mutation damage.

Another type of DNA repair enzyme that may be used is one that is knownto be effective in repairing 06-methyl guanine base mutation damage. Itis sold by AGI/Dermatics under the tradename Adasomes®, and has the INCIname Lactobacillus ferment, which may be added to the composition of theinvention by itself or in admixture with lecithin and water.

Another type of DNA repair enzyme that may be used is one that is knownto be effective in repairing T-T dimers. The enzymes are present inmixtures of biological or botanical materials. Examples of suchingredients are sold by AGI/Dermatics under the tradenames Ultrasomes®or Photosomes®. Ultrasomes® comprises a mixture of Micrococcus lysate(an end product of the controlled lysis of a species of micrococcus),lecithin, and water. Photosomes® comprises a mixture of plankton extract(which is the extract of a biomass which includes enzymes from one ormore of the following organisms: thalassoplankton, green micro-algae,diatoms, greenish-blue and nitrogen-fixing seaweed), water, andlecithin.

Another type of DNA repair enzyme may be a component of variousinactivated bacterial lysates such as Bifida lysate or Bifida fermentlysate, the latter a lysate from Bifido bacteria which contains themetabolic products and cytoplasmic fractions when Bifido bacteria arecultured, inactivated and then disintegrated. This material has the INCIname Bifida Ferment Lysate.

Other suitable DNA repair enzymes include Endonuclease V, which may beproduced by the denV gene of the bacteriophage T4. Also suitable are T4endonuclease; O-6-methylguanine-DNA methyltransferases; photolyases,base glycosylases such as uracil- and hypoxanthine-DNA glycosylases;apyrimidinic/apurinic endonucleases; DNA exonucleases, damaged-basesglycosylases (e.g., 3-methyladenine-DNA glycosylase); correndonucleaseseither alone or in complexes (e.g., E. coli uvrA/uvrB/uvrC endonucleasecomplex); APEX nuclease, which is a multi-functional DNA repair enzymeoften referred to as “APE”; dihydrofolate reductase; terminaltransferase; polymerases; ligases; and topoisomerases.

Other types of suitable DNA repair enzymes may be categorized by thetype of repair facilitated and include BER (base excision repair) or BERfactor enzymes such as uracil-DNA glycosylase (UNG); single strandselective monofunctional uracil DNA glycosylase (SMUG1);3,N(4)-ethenocytosine glycosylase (MBD4); thymine DNA-glycosylase (TDG);A/G-specific adenine DNA glycosylase (MUTYH); 8-oxoguanine DNAglycosylase (OGG1); endonuclease III-like (NTHL1); 3-methyladenine DNAglycosidase (MPG); DNA glycosylase/AP lyase (NEIL1 or 2); APendonuclease (APEX 1 and 2), DNA ligase (LIG3), ligase accessory factor(XRCC1); DNA 5′-kinase/3′-phosphatase (PNKP); ADP-ribosyltransferase(PARP1 or 2).

Another category of DNA repair enzymes includes those that are believedto directly reverse damage such as O-6-MeG alkyl transferase (MGMT);1-meA dioxygenase (ALKBH2 or ALKBH3).

Yet another category of enzymes operable to repair DNA/proteincrosslinks includes Tyr-DNA phosphodiesterase (TDP1).

Also suitable are MMR (mismatch excision repair) DNA repair enzymes suchas MutS protein homolog (MSH2); mismatch repair protein (MSH3); mutShomolog 4 (MSH4); MutS homolog 5 (MSH5); or G/T mismatch-binding protein(MSH6); DNA mismatch repair protein (PMS1, PMS2, MLH1, MLH3);Postmeiotic segregation increased 2-like protein (PMS2L3); orpostmeiotic segregation increased 2-like 4 pseudogene (PMS2L4).

Also suitable are DNA repair enzymes are those known as nucleotideexcision repair (NER) enzymes and include those such as XerodermaPigmentosum group C-complementing protein (XPC); RAD23 (S. cerevisiae)homolog (RAD23B); caltractin isoform (CETN2); RFA Protein 1, 2, of 3(RPA1, 2, or 3); 3′ to 5′ DNA helicase (ERCC3); 5′ to 3′ DNA helicase(ERCC2); basic transcription factor (GTF2H1, GTF2H2, GTF2H3, GTF2H4,GTF2HS); CDK activating kinase (CDK7, CCNH); cyclin G1-interactingprotein (MNAT1); DNA excision repair protein ERCC-1 or RAD-51; excisionrepair cross-complementing 1 (ERCC1); DNA ligase 1 (LIG1); ATP-dependenthelicase (ERCC6); and the like.

Also suitable may be DNA repair enzymes in the category that facilitatehomologous recombination and include, but are not limited to DNA repairprotein RAD51 homolog (RAD51, RAD51L1, RAD51B etc.); DNA repair proteinXRCC2; DNA repair protein XRCC3; DNA repair protein RAD52; ATPase(RAD50); 3′ exonuclease (MRE11A); and so on.

DNA repair enzymes that are DNA polymerases are also suitable andinclude DNA polymerase beta subunit (POLB); DNA polymerase gamma (POLG);DNA polymerase subunit delta (POLD1); DNA polymerase II subunit A(POLE); DNA polymerase delta auxiliary protein (PCNA); DNA polymerasezeta (POLZ); MAD2 homolog (REV7); DNA polymerase eta (POLH): DNApolymerase kappa (POLK): and the like.

Various types of DNA repair enzymes that are often referred to as“editing and processing nucleases” include 3′-nuclease; 3′-exonuclease;5′-exonuclease; endonuclease; and the like.

Other examples of DNA repair enzymes include DNA helicases includingsuch as ATP DNA helicase and so on.

The DNA repair enzymes may be present as components of botanicalextracts, bacterial lysates, biological materials, and the like. Forexample, botanical extracts may contain DNA repair enzymes.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLES Example I Preparation of a Skin-Lightening Composition

TABLE II SKIN-LIGHTENING COMPOSITION MATERIAL WEIGHT PERCENT Phase IWater/phenyl trimethicone/dicapryl carbonate/ 51.0000cimethicone/phospholipids Sodium dehydroacetate 0.1000 Disodium EDTA0.1400 Phase II Glycerin 3.0000 Omeprazole 0.0035 Aluminum starchoctenylsuccinate 1.0000 Phase III Purified water 40.8065Acrylates/C10-30 alkyl acrylate crosspolymer 0.3000 Carbomer 0.3500Phase IV Glycerin 1.0000 Xanthan gum 0.2000 Phase V Purified water2.0000 Triethanolamine 0.1000 TOTAL 100.0000

Procedure:

In main kettle, heat Phase I ingredients to 60° C. and mix untiluniform. In a separate kettle, premix Phase II ingredients until uniformand add to main kettle. Premix Phase III ingredients until uniform andadd into main kettle. Premix Phase IV ingredients until uniform and addinto main kettle. Mix batch in main kettle with a homogenizing mixer for15 minutes while maintaining the temperature at 60° C. Premix Phase Vingredients until clear. Cool the batch in the main kettle to 30° C. AddPhase V ingredients to the batch and mix until uniform. The final pH ofthe batch is 5.35.

Example 2 Clinical Study

This study was designed to determine the skin lightening efficacy of the2-pyridylmethylsulfinyl-benzimidazoles.

Ten female volunteers, aged 18-45 and having skin type I-II(Fitzpatrick, T. B., Ultraviolet-induced Pigmentary Changes: benefitsand hazards, Curr. Probl. Dermatol. 15:25-38, 1986) were recruited froma local population in New York State. Qualified panelists were in normalhealth with no evidence of acute or chronic disease includingdermatologic problems. Subjects exhibiting current sunburn, rashes,scratches, burn marks, etc., which might interfere with the evaluationof test results were excluded from the study. Pregnant or lactatingfemales were also excluded. On examination, the test site of eachsubject was devoid of excessive warts, nevi, moles, sunburn, suntan,scars and active dermal lesions. The panelists were not using systemicor topical retinoids, antihistamines or similar agents currently, hadnot been using such products for at least two weeks prior tocommencement of the study, and agreed that they will not use suchproducts during the course of the study. The subjects expressedwillingness to cooperate with the investigator and demonstrated theability to understand the purpose of the study and the risks associatedwith participating in the study. Panelists signed an informed consentform prior to the initiation of the study.

Distinct areas (approximately 4 cm²) corresponding to the test materialswere marked on the backs of the panelists. Additional sites were markedas the untreated, unirradiated and the untreated, irradiated sites. Thesites were exposed to a single irradiation exposure of 3.5 MEDs of UVB.The source of radiation was a Xenon Arc Solar Simulator (150 Watt) withfilters (mm UG-5) to expose the skin to UV-B and UV-A irradiation.Immediately after irradiation, the sites were treated with the testmaterials every day (with the exception of Saturdays and Sundays) forfour weeks. Test material 1 is the formulation in Table II of Example 1.Comparative Test material 1 is provided below in Table III. Chromameterreadings (reflectance values) were obtained using a Minolta Chromametertwice a week for four weeks. The Chromameter measures the difference inreflectance, L*, of the skin. The change in the value of the differencein reflectance, ΔL* on each of the days on which measurements are takenis measured against a baseline skin color value of the untreatedunirradiated skin measured at every time point. The observed reflectancevalues for all time points are recorded on a graph, and the area underthe curve for each test site is calculated. The skin-lightening factoris calculated as the area under the curve of the treated site subtractedfrom the area under the curve of the untreated site.

As shown in the FIGURE, the composition containing the omeprazoleexhibited an excellent skin-lightening effect at both 3 weeks and 4weeks of treatment, having respective lightening factors of 3.08 and4.63. In contrast, the comparative test formulation containing kojicacid (more than 500 times the concentration of the omeprazole) exhibitedlightening indices of 2.01 and 3.14 at 3 weeks and 4 weeks,respectively.

The results obtained using the omeprazole-containing formula areparticularly impressive in comparison with the results obtained inanother study using 4% hydroquinone. The lightening factors observed forthe hydroquinone were 3.2 and 5.0, at 3 weeks and 4 weeks of treatment,respectively.

TABLE III COMPARATIVE SKIN-LIGHTENING COMPOSITION MATERIAL WEIGHTPERCENT Phase I Water/phenyltrimethicone/cyclomethicone/ 50.00dimethiconol/phosphoglycerides/ carbomer/triethanolamine Sodiumdehydroacetate 0.10 Disodium EDTA 0.14 Phase II Glycerin 3.00 Aluminumstarch octenylsuccinate 1.00 Phase III Purified water 39.81Acrylates/C10-30 alkyl acrylate crosspolymer 0.30 Carbomer 0.35 Kojicacid 2.00 Phase IV Glycerin 1.00 Xanthan gum 0.20 Phase V Purified water1.00 Triethanolamine 0.20 TOTAL 100.00

Procedure:

In main kettle, heat Phase I ingredients to 60° C. and mix untiluniform. In a separate kettle, premix Phase II ingredients until uniformand add to main kettle. Premix Phase III ingredients until uniform andadd into main kettle. Premix Phase IV ingredients until uniform and addinto main kettle. Mix batch in main kettle with a homogenizing mixer for15 minutes while maintaining the temperature at 60° C. Premix Phase Vingredients until clear. Cool the batch in the main kettle to 30° C. AddPhase V ingredients to the batch and mix until uniform. The final pH ofthe batch is 5.12.

That omeprazole can be used in a formulation to lighten the skin is asurprising and unexpected discovery, since one skilled in the art couldnot have predicted that a stomach acid inhibitor would be at least aseffective as a standard lightening agent, kojic acid (which is used atalmost 600 times the concentration of omeprazole) and comparable to theuse of a formulation containing 4% hydroquinone (which is used at morethan 1,000 times the concentration of omeprazole, and above the 2% legallimit for its use in consumer products).

The mechanism of action of the inhibitors of Type I H+, K+-ATPases inskin lightening/depigmentation is under investigation. The inventorshave previously determined that, while 250 μg/ml of omeprazole isrequired to moderately inhibit human tyrosinase activity in test tubeassay using extracts from human melanocytes, to inhibit melanogensis incultured melanocytes, the effective concentration of omeprazole isapproximately 5-50 μg/ml. Therefore, the mechanism of inhibition ofmelanogenesis by omeprazole does not appear to be direct inhibition oftyrosinase activity. Additionally, the inventors have determined, bytreating cells with omeprazole, extracting the total RNA and measuringthe levels of tyrosinase or MITF specific mRNA using gene-specificcomplementary primers and RT-PCR, that omeprazole does not changetyrosinase or MITF mRNA levels in B16F10 mouse melanoma cells.Omeprazole decreases tyrosinase protein level, as determined by analysiswith Western blots using antibodies specific for mouse tyrosinase. Itwas also observed, using an assay for tyrosinase with L-DOPA as asubstrate, that omeprazole decreases the tyrosinase activity of B16F10cell extracts. It is possible that the pH of the melanosome, aside fromregulating tyrosinase activity, also regulates trafficking andmaturation of tyrosinase. Thus, a change in pH may also reduce theamount of tyrosinase protein as well as decreasing its activity.

Ancans et al. (2001), supra, has suggested that, as the p-locus protein(which may be a Na+/H+ antiporter) in melanosomes mediates theneutralization of melanosomal pH, this protein could be a key controlpoint for skin pigmentation. However, this protein too does not appearto be the target for omeprazole. The inventors have demonstrated, byprotein sequence comparison with the known target protein of omeprazolein human parietal cells, that the p-locus protein and the gastric pumphave no sequence homology, that is, there are no cysteines in thep-locus protein, which are comparable to those in the gastric pump, tobind omeprazole. The inventors have further determined that the onlyknown target for omeprazole binding, the protein ATP4A (gastric pump),does not appear to be expressed in human melanocytes because, asdetermined using gene-specific primers and RT-PCR, the mRNA for thegastric pump is not found in melanocytes. Thus, surprisingly, the PPIinhibitor compounds may not function in the same way in the melanosome(if the target is in the melanosome) as they do in the parietal cells ofthe stomach. Studies of proteins ATPA7 and ATP12A, which are alsopresent in gastric parietal cells, and which are structurally related toATP4A, indicate that each of these pumps do not contain cysteines in alocus appropriate for omeprazole binding. Thus the mechanism of actionof omeprazole and other inhibitors of Type I H+, K+-ATPases ininhibiting melanogenesis is novel and unexpected from any of the priorart teachings.

While the subject invention have been described in various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions and changes may be made withoutdeparting from the spirit thereof.

1. A topically applicable composition for lightening or depigmentingskin, comprising a skin lightening or depigmenting effective amount ofat least one compound represented by the structural formula:

wherein: R₂ is hydrogen, lower alkyl or hydroxy lower alkyl; R₃ is loweralkyl, —CH₂CN, hydroxy lower alkyl, —NO, —CH₂N═C or

(wherein R₆ and R₇ are independently selected from the group consistingof hydrogen and lower alkyl) or hydrogen provided R₂ is not hydrogen; R₄is Z-T-W wherein Z represents —O—, —NH— or a single bond; T represents astraight- or branched-chain lower-alkylene group; when Z is a singlebond, T also represents an ethenylene or a propenylene group wherein theunsaturated carbon is at the single bond; when Z is —O—, T alsorepresents an allylene group wherein the saturated carbon is at theoxygen; and W represents hydrogen, when T is allylene and Z is —O—, orAr, wherein Ar is selected from thienyl, pyridinyl, furanyl, phenyl andsubstituted phenyl wherein there are one or more substituents on thephenyl independently selected from halogen or lower alkyl; and R₅ ishydrogen, halogen or lower alkyl; or SCH32651(3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine; or a derivativeor physiologically acceptable salt, solvate or bioprecursor, or anystereoisomer or enantiomer thereof; formulated into a topicallyapplicable, cosmetically or dermatologically acceptable vehicle, carrieror diluent therefor.
 2. The composition of claim 1, wherein R₂ of thecompound of formula (II) is methyl or ethyl; R₃ is —NH₂, —NHC₂H₅,—CH₂CN, —CH₃, —CH₂OH or —CH₂N═C; R4 is —OCH₂Ar, —NHCH₂Ar,—CH═CH—(CH₂)_(n) Ar or —CH₂CH₂(CH₂)_(n)Ar wherein n is zero or one andAr is as defined in claim 1; and R₅ is hydrogen, fluoro, chloro ormethyl.
 3. The composition of claim 1, wherein R₄ of the compound offormula (II) is at the 8-position and is selected from phenylmethoxy,phenylethyl, 3-phenyl-1-propenyl, phenylethenyl, benzylamino,3-thienylmethoxy and 3-thienylmethanamino; R₂ is methyl; R₃ is amino,cyanomethyl or methyl; and R₅ is hydrogen or methyl at the 7-position.4. The composition of claim 1, wherein the compound of the formula (II)is selected from the group consisting of SCH 28080(3-(cyanomethyl)-2-methyl-8-phenylmethoxy-imidazo[1,2-a]pyridine); andSCH 32651 (3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine). 5.The composition of claim 1, which is in the form of an anhydrouscomposition, an aqueous-based solution, suspension, dispersion, lotion,serum, essence, emulsion, milk, cream, gel, paste, ointment, spray,stick, mousse, aerosol or microcapsules.
 6. The composition of claim 1,further comprising at least one cosmetic or dermatological active,additive or adjuvant.
 7. The composition of claim 1, wherein thecompound of the formula (II) or derivative thereof is an imidazopyridinederivative selected from the group consisting of3-amino-2-methyl-8-(2-phenylethyl)imidazo-[1,2-a]pyridine;2,3-dimethyl-8-[(2-phenyl)ethenyl]imidazo[1,2-a]pyridine;3-cyanomethyl-2-methyl-8-(3-phenyl-1-propenyl)imidazo[1,2-a]pyridine;2,7-dimethyl-8-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;3-ethylamino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;3-ethylamino-2-methyl-8-(2-phenylethyl)-imidazo[1,2-a]pyridine;3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;3-amino-2-ethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;3-amino-2,6-dimethyl-8-phenylmhethoxyimidazo[1,2-a]pyridine;3-amino-2,7-dimethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;3-amino-8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;3-amino-8-(4-chlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;3-amino-2-methyl-8-[(3-thienylethyl)amino]imidazo[1,2-a]pyridine;3-amino-2-methyl-8-(3-thienylmethoxy)imidazo[1,2-a]pyridine;3-amino-2-methyl-8-(2-thienylmethoxy)imidazo[1,2-a]pyridine;2-methyl-3-isocyanomethyl-8-phenylmethoxyimidazo[1,2-a]pyridine;2-methyl-8-[3-thienylmethylamino]-imidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-6-(2-phenylethyl)-imidazo[1,2-a]pyridine-3-acetonitrile;3-amino-2-methyl-6-(2-phenylethyl)-imidazo[1,2-a]pyridine;3-amino-8-(4-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;2-methyl-8-(2,4,6-trimethylphenylmethoxy)imidazo[1,2-a]pyridine;8-(3,4-dichlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;8-(4-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine;8-(4-chlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;2-methyl-8-(2-thienylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-8-(2-pyridylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;8-(3,4-dichlorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;8-(4-methoxyphenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;8-(4-t-butylphenylmethoxy-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;8-(4-chlorophenylmethoxy)-methylimidazo[1,2-a]pyridine-3-acetonitrile;8-(3,4-dichlorophenyhmethoxy)-3-hydroxymethy-2-methylimidazo[1,2-a]pyridine;8-(4-chlorophenylmethoxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;8-phenylmethoxy-2-ethylimidazo[1,2-a]pyridine;8-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;8-phenylmethoxy-2-hydroxymethylimidazo[1,2-a]pyridine;3-hydroxymethyl-2-methyl-8-(2-phenylethoxy)imidazo[1,2-a]pyridine;8-phenylmethoxy-2,3-dimethylimidazo[1,2-a]pyridine;2-methyl-8-(2-phenylethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-8-(1-phenylethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine-3-acetonitrile;3-hydroxymethyl-2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine;2-methyl-8-(3-phenylpropoxyl)imidazo[1,2-a]pyridine-3-acetonitrile;8-phenylmethoxy-2-isopropylimidazo[1,2-a]pyridine-3-acetonitrile;8-phenylmethoxy-2-ethylimidazo[1,2-a]pyridine-3-acetonitrile;8-benzylamino-2,3-dimethylimidazo[1,2-a]pyridine;8-phenylmethoxy-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;8-phenylmethoxy-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;3-hydroxymethyl-8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine;8-(4-t-butylbenzyloxy)-3-hydroxymethyl-2-methylimidazo[1,2-a]pyridine;8-(2-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;8-(4-fluorophenylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-8-(2,4,6-trimethylphenylmethoxy)imidazo[1,2-a]pyridine-2-acetonitrile;8-benzylamino-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-8-(3-thienylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;8-allyloxy-2-methylimidazo[1,2-a]pyridine-3-acetonitrile;2-ethyl-8-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;2-ethyl-3-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine;3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyridine and the phosphateacid addition salt thereof;2-methyl-8-(3-phenylpropyl)imidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-6-benzylaminoimidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-6-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-5-benzylaminoimidazo[1,2-a]pyridine-3-acetonitrile;2-methyl-5-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;2,3-dimethyl-5-phenylmethoxyimidazo[1,2-a]pyridine;2-methyl-7-phenylmethoxyimidazo[1,2-a]pyridine-3-acetonitrile;3-(cyanomethyl)-2-methyl-8-phenylmethoxy-imidazo[1,2-a]pyridine; and3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine.
 8. A topicallyapplicable composition for lightening or depigmenting skin, comprising askin lightening or depigmenting effective amount of at least onecompound selected from the group consisting of SCH 28080(3-(cyanomethyl)-2-methyl-8-phenylmethoxy-imidazo[1,2-a]pyridine); SCH32651 (3-amino-2-methyl-8-phenylmethoxyimidazo[1,2-a]pyrazine)soraprazan([(7R,8R,9R)-2,3-dimethyl-8-hydroxy-7(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydro-imidazo-[1,2-h][1,7]-naphthyridine]);pumaprazole(8-(2-methoxycarbonylamino-6-benzulamino)-2,3-dimethylimidazo-[1,2-a)pyridine-D,L-hemimalate];AR-H047108((8-[(2-ethyl-6-methylbenzyl)amino]2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide);dapiprazole(3-{2-[4-(2-methylphenyl)piperazin-1-yl]ethyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,5-a]pyridine);AZD0865((8-[2,6-dimethylbenzyl)amino]-N-(2-hydroxyethyl)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide);tenatoprazole(3-methoxy-8-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methylsulfinyl]-2,7,9-triazabicyclo[4.3.0]nona-2,4,8,10-tetraene);aripiprazole(7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one);revaprazan([5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl-pyrimidine]);and CS-526(7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine),formulated into a topically applicable, cosmetically or dermatologicallyacceptable vehicle, carrier or diluent therefor.
 9. The composition ofclaim 8, comprising an additional cosmetic ingredient selected fromskin-lightening agents and sun protection agents.
 10. The composition ofclaim 8, in the form of an emulsion.